Compositions Containing Satiogens and Methods of Use

ABSTRACT

Provided herein are methods and compositions for treating metabolic diseases and conditions associated with metabolic diseases.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application Nos.61/118,324, filed Nov. 26, 2008, and 61/255,211, filed Oct. 27, 2009,each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Obesity is a medical condition affecting numerous humans in a number ofcountries throughout the world, and is associated with or induces otherdiseases or conditions. In particular, obesity is a serious risk factorfor diseases and conditions such as diabetes, hypertension, gallbladderdisease, cancer, polycystic ovary disease and arteriosclerosis and cancontribute to elevated levels of cholesterol in the blood. In addition,increased body weight due to obesity places a burden on joints causingarthritis, pain, and stiffness. Overeating and obesity have become aproblem in the general population, consequently there is interest inlosing weight, reducing weight, and/or maintaining a healthy body weightand lifestyle.

SUMMARY OF THE INVENTION

Provided in certain embodiments herein is a pharmaceutical compositioncomprising:

-   -   a. a therapeutically effective amount of an enteroendocrine        peptide secretion enhancing agent;    -   b. an absorption inhibitor of the enteroendocrine peptide        secretion enhancing agent; and    -   c. a carrier.

In some embodiments, the pharmaceutical composition is formulated fornon-systemic rectal or colonic delivery of the enteroendocrine peptidesecretion enhancing agent. In certain embodiments, the enteroendocrinepeptide secretion enhancing agent is a bile acid, a bile salt, a bileacid mimic, a bile salt mimic, or a combination thereof. In someembodiments, the enteroendocrine peptide secretion enhancing agent is aglucogen-like peptide secretion enhancing agent, optionally incombination with a bile acid, a bile salt, a bile acid mimic, or a bilesalt mimic. In certain embodiments, the glucogen-like peptide secretionenhancing agent is a glucogen-like peptide-1 (GLP-1) secretion enhancingagent or a glucogen-like peptide-2 (GLP-2) secretion enhancing agent,optionally in combination with a bile acid, a bile salt, a bile acidmimic, or a bile salt mimic. In some embodiments, the enteroendocrinepeptide secretion enhancing agent is a pancreatic polypeptide-foldpeptide secretion enhancing agent, optionally in combination with a bileacid, a bile salt, a bile acid mimic, or a bile salt mimic. In someembodiments, the pancreatic polypeptide-fold peptide secretion enhancingagent is a peptide YY (PYY) secretion enhancing agent.

In certain embodiments, the composition further comprises at least oneof a cholesterol absorption inhibitor, a spreading agent or a wettingagent. In some embodiments, the absorption inhibitor is a mucoadhesiveagent. In specific embodiments, the polymer having mucoadhesiveproperties is selected from methyl cellulose, polycarbophil,polyvinylpyrrolidone, sodium carboxymethyl cellulose, and combinationsthereof. In some embodiments, the enteroendocrine peptide secretionenhancing agent is covalently linked to the absorption inhibitor.

In certain embodiments, the carrier is a rectally suitable carrier. Incertain embodiments, any pharmaceutical composition described herein isformulated as a suppository, an enema solution, a rectal foam, or arectal gel. In some embodiments, any pharmaceutical compositiondescribed herein comprises an orally suitable carrier. In certainembodiments, the pharmaceutical composition comprises an entericcoating.

In some embodiments, any composition described herein further comprisesan enteroendocrine peptide.

Provided in certain embodiments herein is a method for treating ametabolic disease or a condition associated with a metabolic diseasecomprising administering to the lower ileum, the colon and/or the rectumof an individual in need thereof, a pharmaceutical compositioncomprising a therapeutically effective amount of an enteroendocrinepeptide secretion enhancing agent. Provided in certain embodimentsherein is a method for treating a metabolic disease or a conditionassociated with a metabolic disease comprising administering (e.g.,orally or rectally administering) to an individual in need thereof, apharmaceutical composition comprising a therapeutically effective amountof an enteroendocrine peptide secretion enhancing agent and a carrier.In some embodiments, administered is a pharmaceutical composition thatfurther comprises an absorption inhibitor, wherein the absorptioninhibitor inhibits the absorption of the enteroendocrine peptidesecretion enhancing agent across the rectal or colonic mucosa. In someembodiments, the composition administered comprises an orally suitablecarrier. In certain embodiments, the pharmaceutical composition isformulated for enteric delivery. In some embodiments, the pharmaceuticalcomposition comprises an enteric coating.

Provided in certain embodiments herein is a method for treating obesityor diabetes comprising administering to the lower ileum, the colonand/or the rectum of an individual in need thereof, a pharmaceuticalcomposition comprising a therapeutically effective amount of anenteroendocrine peptide secretion enhancing agent. Provided in someembodiments herein is a method for treating obesity or diabetescomprising administering (e.g., orally or rectally administering) to anindividual in need thereof, a pharmaceutical composition comprising atherapeutically effective amount of an enteroendocrine peptide secretionenhancing agent and a carrier. In some embodiments, administered is apharmaceutical composition that further comprises an absorptioninhibitor, wherein the absorption inhibitor inhibits the absorption ofthe enteroendocrine peptide secretion enhancing agent across the rectalor colonic mucosa. In some embodiments, the composition administeredcomprises an orally suitable carrier. In certain embodiments, thepharmaceutical composition is formulated for enteric delivery. In someembodiments, the pharmaceutical composition comprises an entericcoating.

In some embodiments, administered according to a method described hereinis a composition comprising a rectally suitable carrier. In someembodiments, the administered pharmaceutical composition is formulatedas a suppository, an enema solution, a rectal foam, or a rectal gel.

In certain embodiments, a composition administered according to a methoddescribed herein comprises a enteroendocrine peptide secretion enhancingagent that is a bile acid, bile salt, bile acid mimic or bile saltmimic. In some embodiments, the enteroendocrine peptide secretionenhancing agent is a glucogen-like peptide secretion enhancing agent. Incertain embodiments, the enteroendocrine peptide secretion enhancingagent is a glucogen-like peptide-1 (GLP-1) secretion enhancing agent ora glucogen-like peptide-2 (GLP-2) secretion enhancing agent. In someembodiments, the enteroendocrine peptide secretion enhancing agent is apancreatic polypeptide-fold peptide secretion enhancing agent. Inspecific embodiments, the enteroendocrine peptide secretion enhancingagent is a peptide YY (PYY) secretion enhancing agent. In someembodiments, a composition administered according to a method describedherein comprises any one or more of the enteroendocrine peptidesecretion enhancing agents described herein.

In some embodiments, the composition administered comprises at least oneof a cholesterol absorption inhibitor, a spreading agent or a wettingagent. In some embodiments, the absorption inhibitor is a mucoadhesiveagent (e.g., a mucoadhesive polymer). In certain embodiments, themucoadhesive agent is selected from methyl cellulose, polycarbophil,polyvinylpyrrolidone, sodium carboxymethyl cellulose, and combinationsthereof. In some embodiments, a pharmaceutical composition administeredfurther comprises an enteroendocrine peptide.

In certain embodiments, the enteroendocrine peptide secretion enhancingagent is delivered to and/or the pharmaceutical composition comprisingthe same is administered to the colon, rectum or to the colon and rectumof the individual.

In some embodiments, the condition treated is weight gain, appetite,food intake, impaired glucose tolerance, a glucose metabolic disorder,or insulin resistance. In some embodiments, the metabolic disease isobesity, diabetes or a combination thereof.

Provided in some embodiments herein is a kit comprising any compositiondescribed herein (e.g., a pharmaceutical composition formulated forrectal administration) and a device for localized delivery within therectum or colon. In certain embodiments, the device is a syringe, bag,or a pressurized container.

Provided in some embodiments herein is the use of any pharmaceuticalcomposition described herein in the manufacture of a medicament for thetreatment of a metabolic disorder or a condition associated with ametabolic disorder. In some embodiments, the condition associated with ametabolic disorder is weight gain, appetite, food intake, impairedglucose tolerance, a glucose metabolic disorder, or insulin resistance.In specific embodiments, the metabolic disease is obesity, diabetes or acombination thereof.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings.

FIG. 1 illustrates the response of enteroendocrine peptides toadministration of bile salts. FIG. 1A illustrates the plasma PYYconcentrations in the caecum, transverse colon, and sigmoid as a resultof bile salt administration. FIG. 1B illustrates the plasmaenteroglucagon concentrations in the caecum, transverse colon, andsigmoid as a result of bile salt administration.

FIG. 2 illustrates the affect on food intake of pump infusion of TCA.

FIG. 3 illustrates the affect on body weight of pump infusion of TCA.

FIG. 4 illustrates the affect of the viscosity of a formulationdescribed herein on the food intake of a subject.

FIG. 5 illustrates the cumulative food intake of rats with (dottedlines) and without (solid lines) rectal administration of taurocholate.

FIG. 6 illustrates the cumulative food intake of rats with rectaladministration of three concentrations of taurocholate and thecumulative food intake of rats without rectal administration oftaurocholate.

FIG. 7 illustrates the dose response for the anorectic effect oftaurocholate.

FIG. 8 illustrates the normal GI distribution of PYY (pmol/g).

FIG. 9 illustrates the acute release of GLP-1 in response toadministration of bile acids in obese human diabetics.

FIG. 9 illustrates the acute release of PYY in response toadministration of bile acids in obese human diabetics.

FIG. 11 illustrates the reduction of food intake in response toadministration of bile acids in obese human diabetics.

FIG. 12 illustrates the acute release of insulin and in response toadministration of bile acids in obese human diabetics.

FIG. 13 illustrates the incremental integrated response of insulin tobile acids in obese human diabetics.

FIG. 14 illustrates the acute reduction of glucose in response toadministration of bile acids in obese human diabetics.

FIG. 15 illustrates the incremental integrated response of glucose tobile acids in obese human diabetics.

FIG. 16 illustrates delivery of bile acid salts to the lower gut via abiliary shunt.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

DEFINITIONS

The term “bile acid,” as used herein, includes steroid acids (and/or thecarboxylate anion thereof), and salts thereof, found in the bile of ananimal (e.g., a human), including, by way of non-limiting example,cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholicacid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid,taurocholate, chenodeoxycholic acid, chenodeoxycholate, lithocholicacid, lithocolate, and the like. Taurocholic acid and/or taurocholateare referred to herein as TCA. Any reference to a bile acid used hereinincludes reference to a bile acid, one and only one bile acid, one ormore bile acids, or to at least one bile acid. Therefore, the terms“bile acid,” “bile salt,” “bile acid/salt,” “bile acids,” “bile salts,”and “bile acids/salts” are, unless otherwise indicated, utilizedinterchangeably herein. Any reference to a bile acid used hereinincludes reference to a bile acid or a salt thereof. Furthermore,pharmaceutically acceptable bile acid esters are optionally utilized asthe “bile acids” described herein, e.g., bile acids conjugated to anamino acid (e.g., glycine or taurine). Other bile acid esters include,e.g., substituted or unsubstituted alkyl ester, substituted orunsubstituted heteroalkyl esters, substituted or unsubstituted arylesters, substituted or unsubstituted heteroaryl esters, or the like. Forexample, the term “bile acid” includes cholic acid conjugated witheither glycine or taurine: glycocholate and taurocholate, respectively(and salts thereof). Any reference to a bile acid used herein includesreference to an identical compound naturally or synthetically prepared.Furthermore, it is to be understood that any singular reference to acomponent (bile acid or otherwise) used herein includes reference to oneand only one, one or more, or at least one of such components.Similarly, any plural reference to a component used herein includesreference to one and only one, one or more, or at least one of suchcomponents, unless otherwise noted.

The term “colon,” as used herein, includes the cecum, ascending colon,hepatic flexure, splenic flexure, descending colon, and sigmoid.

The term “composition,” as used herein includes the disclosure of both acomposition and a composition administered in a method as describedherein. Furthermore, in some embodiments, the composition of the presentinvention is or comprises a “formulation,” an oral dosage form or arectal dosage form as described herein.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety may also be an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group consistingof at least two carbon atoms and at least one carbon-carbon double bond,and an “alkyne” moiety refers to a group consisting of at least twocarbon atoms and at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, may be branched, straightchain, or cyclic. Furthermore, the alkyl moiety, whether saturated orunsaturated, may comprise branched, straight chain, and/or cyclicportions. Depending on the structure, an alkyl group can be amonoradical or a diradical (i.e., an alkylene group). A “heteroalkyl”group is as described for “alkyl” with at least one of the C atomsthereof substituted with an N, S, or O atom. The “heteroalkyl” group maycomprise linear, branched, and/or cyclic portions. In certainembodiments, a “lower alkyl” is an alkyl group with 1-6 carbon atoms(i.e., a C₁-C₆ alkyl group). In specific instances, the “lower alkyl”may be straight chained or branched.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,fluorenyl, and indenyl. Depending on the structure, an aryl group can bea monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms. Illustrative examples of cycloalkyl groups include the followingmoieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. The polycyclicheteroaryl group may be fused or non-fused. Illustrative examples ofheteroaryl groups include the following moieties:

and the like. Depending on the structure, a heteroaryl group can be amonoradical or a diradical (i.e., a heteroarylene group).

A “heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one ring atom that is not a carbon, i.e. at least one ring atom isa heteroatom selected from nitrogen, oxygen and sulfur. Theheterocycloalkyl radicals may be fused with an aryl or heteroaryl.Illustrative examples of heterocycloalkyl groups, also referred to asnon-aromatic heterocycles, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Heterocycloalkyls have from 2 to10 carbons in the ring. A “lower heterocycloalkyl” has 2 to 8 ringcarbon atoms. It is understood that when referring to the number ofcarbon atoms in a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same at the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e skeletal atomsof the heterocycloalkyl ring).

The term “modulate,” as used herein refers to having some affect on(e.g., increasing, enhancing or maintaining a certain level).

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from C₁-C₆alkyl,C₃-C₈cycloalkyl, aryl, heteroaryl, C₂-C₆heteroalicyclic, hydroxy,C₁-C₆alkoxy, aryloxy, C₁-C₆alkylthio, arylthio, C₁-C₆alkylsulfoxide,arylsulfoxide, C₁-C₆alkylsulfone, arylsulfone, cyano, halo, C₂-C₈acyl,C₂-C₈acyloxy, nitro, C₁-C₆haloalkyl, C₁-C₆-fluoroalkyl, and amino,including C₁-C₆alkylamino, and the protected derivatives thereof. By wayof example, an optional substituents may be L^(s)R^(s), wherein eachL^(s) is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂—, —OC(═O)NH—,—NHC(═O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and each R^(s) isindependently selected from H, (C₁-C₄alkyl), (C₃-C₈cycloalkyl),heteroaryl, aryl, and C₁-C₆heteroalkyl. Optionally substitutednon-aromatic groups may be substituted with one or more oxo (═O). Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above. In some embodiments, alkylgroups described herein are optionally substituted with an O that isconnected to two adjacent carbon atoms (i.e., forming an epoxide).

The term “therapeutically effective amount” or an “effective amount” asused herein, refers to a sufficient amount of a therapeutically activeagent to provide a desired effect in a subject or individual. In someembodiments, a “therapeutically effective amount” or an “effectiveamount” of an enteroendocrine peptide secretion enhancing agent refersto a sufficient amount of the enteroendocrine peptide secretionenhancing agent to a treat a metabolic disorder in a subject orindividual. In some embodiments, a “therapeutically effective amount” oran “effective amount” of an enteroendocrine peptide secretion enhancingagent refers to a sufficient amount of the enteroendocrine peptidesecretion enhancing agent to increase the secretion of enteroendocrinepeptide(s) in a subject or individual. In specific embodiments, the“therapeutically effective amount” is an amount that when delivered tothe colon or rectum it produces an anorectal response (e.g., it increasethe secretion of enteroendocrine peptide(s) in the rectum and/or colon,particularly in the L-cells, of an individual). In some embodiments, a“therapeutically effective amount” or an “effective amount” of anenteroendocrine peptide secretion enhancing agent refers to a sufficientamount of the enteroendocrine peptide secretion enhancing agent todecrease hunger in a subject, to curb appetite in a subject and/ordecrease the food intake of a subject or individual.

Enteroendocrine Peptide Secretion L-Cells

L-cells are scattered throughout the epithelial layer of the gut fromthe duodenum to the rectum, with the highest numbers occurring in theileum, colon, and rectum. They are characterized by an open-cellmorphology, with apical microvilli facing into the gut lumen andsecretory vesicles located adjacent to the basolateral membrane, and aretherefore in direct contact with nutrients in the intestinal lumen.Furthermore, L-cells are located in close proximity to both neurons andthe microvasculature of the intestine, thereby allowing the L-cell to beaffected by both neural and hormonal signals. As well as Glucagon-LikePeptide 1 (GLP-1) and Glucagon-Like Peptide 2 (GLP-2), L-cells alsosecrete the anorexigenic hormone, peptide YY (PYY), and glutamate. Thecells are just one member of a much larger family of enteroendocrinecells that secrete a range of hormones, including ghrelin, GIP,cholecystokinin, somatostatin, and secretin, which are involved in thelocal coordination of gut physiology, as well as in playing wider rolesin the control of insulin release and appetite. L-cells are unevenlydistributed in the gastrointestinal tract, within higher concentrationsin the distal portion of the gastrointestinal tract (e.g., in the distalileum, colon and rectum).

Proglucagon Products

The proglucagon gene product is expressed in the L-cells of the smallintestine, in α-cells of the pancreas and in the central nervous system.Tissue-specific expression of isoforms of the enzyme prohormoneconvertase directs posttranslational synthesis of specificproglucagon-derived peptides in the L-cell and α-cell. Specifically,cleavage of proglucagon by prohormone convertase ⅓, which is expressedin the L-cell, forms GLP-1 and GLP-2, as well as the glucagon-containingpeptides, glicentin and oxyntomodulin. In contrast, α-cell expression ofprohormone convertase 2 forms glucagon, glicentin-related pancreaticpeptide, and the major proglucagon fragment, which contains within itssequence both the GLP-1 and GLP-2 sequences.

Glucagon-like peptide 1 (GLP-1) is an intestinal hormone that effects inthe regulation of glycemia, stimulating glucose-dependent insulinsecretion, proinsulin gene expression, and B-cell proliferative andanti-apoptotic pathways, as well as inhibiting glucagon release, gastricemptying, and food intake. The anorexigenic effect of GLP-1 is mediatedby GLP-1 receptors which are present in both the NTS and hypothalamus,and in the pancreas, lung, brain, kidney, gastrointestinal tract andheart. Reduced secretion of GLP-1 contributes to the pathogenesis ofobesity and enhanced/or normal secretion restores satiety.

The primary physiological stimulus of GLP-1 secretion from L-cells isingestion of carbohydrates, luminal glucose (not systemic glucose) fat,and protein. Protein hydrolysate are also potent triggers of GLP-1release, and certain amino acids such as, but not limited to, alanine,serine, glutamine, asparagine, and glycine stimulate GLP-1 release.Within the fat group, the long-chain unsaturated fatty acid andshort-chain fatty acid subgroups are potent triggers of GLP-1 release,while the short-chain fatty acids also stimulate peptide YY release. Inaddition to luminal nutrients, intestinal peptides, neurotransmitters,as well as systemic hormones, modulate GLP-1 secretion. Such intestinalpeptides include, but are not limited to, somatostatin (forms SS14 andSS28), and such neurotransmitters include, but are not limited to,acetylcholine and γ-aminobutyric acid (GABA) (both of which enhanceGLP-1 release), and α- and β-adrenergic agonists, (which respectivelyinhibit and/or stimulate GLP-1 secretion from L-cells). Peripheralhormones that participate in energy homeostasis, such as the adipocytehormone leptin, also stimulate GLP-1 release. Other GLP-1 secretegouesinclude bile acids/salts, insulin, gastrin-releasing peptide (GRP),several gut peptides including, but not limited to, Gastric InhibitoryPolypeptide (GIP) and calcitonin gene-related protein (CGRP). CGRP is apeptide found throughout the enteric nervous system. Thus, GLP-1secretagogues include, but are not limited to, nutrients,neurotransmitters, neuropeptides, intestinal peptide, peripheralhormones, and bile acis/salts.

Within about 15 minutes of food ingestion the circulating GLP-1 levelsincrease and remain elevated for up to 3 hours, depending on thecomposition of the meal. Circulating GLP-1 exists in two equipotentforms, GLP-1^(7-36NH2) and GLP-1⁷⁻³⁷, with GLP-1^(7-36NH2) being thepredominant form. Secreted GLP-1 is rapidly degraded by the ubiquitousenzyme dipeptidyl peptidase-4 (DPP-4), resulting in an extremely shorthalf-life for GLP-1 of about 30 seconds to about 2 minutes. Therefore,levels of circulating GLP-1 are maintained by inhibiting DPP-4 activity,or alternatively, by enhancing GLP-1 secretion.

In some embodiments, provided herein is a method of increasingcirculating GLP (e.g., GLP-1) levels by administering to the distalgastrointestinal tract (e.g., distal ileum, colon and/or rectum) aneffective amount of an enteroendocrine peptide secretion enhancing agent(e.g., a bile acid). In certain embodiments, the method is included in amethod of treating a metabolic disorder. In some embodiments, the methodis included in a method of treating obesity or diabetes. FIG. 9illustrates the increase of circulating GLP-1 levels following rectaladministration of an enteroendocrine peptide secretion enhancing agent(e.g., a bile acid). FIG. 9 illustrates the increase of circulatingGLP-1 levels following rectal administration of taurocholic acid.

Pancreatic Polypeptide (PP)-Fold Peptides

The Pancreatic Polypeptide (PP)-fold peptides include Peptide YY (PYY),Pancreatic Polypeptide (PP) and Neuropeptide Y (NPY), which all sharesequence homology and contain several tyrosine residues. They have acommon tertiary structure which consists of an α-helix and polyprolinehelix, connected by a B-turn, resulting in a characteristic U-shapedpeptide, the PP-fold.

Neuropeptide Y (NPY) is one of the most abundant neurotransmitters inthe brain. Hypothalamic levels of NPY reflect the body's nutritionalstatus, wherein the levels of hypothalamic NPY mRNA and NPY releaseincrease with fasting and decrease after feeding.

Pancreatic Polypeptide (PP) is produced by cells at the periphery of theislets of the endocrine pancreas, and to a lesser extent in the exocrinepancreas, colon and rectum. The release of PP is biphasic and occurs inproportion to the number of calories ingested, with the levels remainingelevated for up to 6 hours post-prandially. The circulating levels of PPare increased by gastric distension, ghrelin, motilin and secretin andreduced by somatostatin. In addition, circulating PP exhibits a diurnalrhythm, with levels low in the early hours of the morning and highest inthe evening. The levels of PP have been found to reflect long-termenergy stores, with lower levels and reduced second phase of release inobese subjects, and higher levels in anorexic subjects. Circulating PPis unable to cross the blood-brain barrier, but exerts its anorecticeffect by sending anorectic signals via brainstem pathways, hypothalamicneuropeptides and by modulating expression of other gut hormones such asghrelin.

Peptide YY (PYY) is secreted predominantly from the distalgastrointestinal tract, particularly the ileum, colon and rectum. FIG. 8illustrates the concentration of PYY at various locations in thegastrointestinal tract. The L-cells of the intestine release PYY inproportion to the amount of calories ingested, and occurs before thenutrients reach the cells in the distal tract. Thus, release may bemediated via a neural reflex as well as direct contact with nutrients.Post-prandially, the circulating PYY levels rise rapidly to a plateauafter 1-2 hours and remain elevated for up to 6 hours. The levels of PYYare also influenced by meal composition, with higher levels obtainedfollowing fat intake relative to carbohydrate or protein intake. Othersignals, such as gastric acid, CCK and luminal bile salts, insulin-likegrowth factor 1, bombesin and calcitonin-gene-related peptide increasePYY levels, whereas gastric distension has no effect, and levels arereduced by GLP-1. The N-terminal of circulating PYY allows it to crossthe blood-brain barrier.

In some embodiments, provided herein is a method of increasingcirculating PYY levels by administering to the distal gastrointestinaltract (e.g., distal ileum, colon and/or rectum) an effective amount ofan enteroendocrine peptide secretion enhancing agent (e.g., a bileacid). In certain embodiments, the method is included in a method oftreating a metabolic disorder. In some embodiments, the method isincluded in a method of treating obesity or diabetes. FIG. 10illustrates the increase of circulating PYY levels following rectaladministration of an enteroendocrine peptide secretion enhancing agent(e.g., a bile acid).

Enteroendocrine Peptide Secretion Enhanced Treatment

Intravenous administration of GLP-1 decreases food intake in both leanand obese individuals in a dose-dependent manner, although the effect issmall when infusions achieve post-prandial circulating levels. Inaddition, obese subjects given subcutaneous GLP-1 prior to each meal,reduce their caloric intake. Thus, modulation/control of GLP-1 secretionrestore satiety and controls appetite and food intake. Similarly,infusion of PP decreases appetite and food intake. Obese humans have arelatively low level of circulating PYY and a relative deficiency ofpost-prandial secretion of PYY. Administration of PYY causes a delay ingastric emptying, a delay in secretions from the pancreas and stomach,and increases the absorption of fluids and electrolytes from the ileumafter a meal. In addition, intravenous administration of PYY decreasesappetite, inhibits food intake and reduces weight gain.

Appetite, weight gain and food intake are controlled by the circulatingor systemic levels of GLP-1, PYY and PP. The methods and compositiondescribed herein use, by way of non-limiting example, the administrationof bile acids/salts and bile acids/salts mimics to modulate (e.g.,increase) the circulating levels of GLP-1, PYY and PP. In certainembodiments of the present invention, such administration decreases foodintake and weight gain while suppressing appetite.

Bile Acid

Bile contains water, electrolytes and a numerous organic moleculesincluding bile acids, cholesterol, phospholipids and bilirubin. Bile issecreted from the liver and stored in the gall bladder, and upon gallbladder contraction, due to ingestion of a fatty meal, bile passesthrough the bile duct into the intestine. Bile acids are critical fordigestion and absorption of fats and fat-soluble vitamins in the smallintestine. Adult humans produce 400 to 800 mL of bile daily. Thesecretion of bile can be considered to occur in two stages. Initially,hepatocytes secrete bile into canaliculi, from which it flows into bileducts and this hepatic bile contains large quantities of bile acids,cholesterol and other organic molecules. Then, as bile flows through thebile ducts, it is modified by addition of a watery, bicarbonate-richsecretion from ductal epithelial cells. Bile is concentrated, typicallyfive-fold, during storage in the gall bladder.

The flow of bile is lowest during fasting, and a majority of that isdiverted into the gallbladder for concentration. When chyme from aningested meal enters the small intestine, acid and partially digestedfats and proteins stimulate secretion of cholecystokinin and secretin,both of which are important for secretion and flow of bile.Cholecystokinin (cholecysto=gallbladder and kinin=movement) is a hormonewhich stimulates contractions of the gallbladder and common bile duct,resulting in delivery of bile into the gut. The most potent stimulus forrelease of cholecystokinin is the presence of fat in the duodenum.Secretin is a hormone secreted in response to acid in the duodenum, andit simulates biliary duct cells to secrete bicarbonate and water, whichexpands the volume of bile and increases its flow out into theintestine.

Bile acids are derivatives of cholesterol. Cholesterol, ingested as partof the diet or derived from hepatic synthesis, are converted into bileacids in the hepatocyte. Examples of such bile acids include cholic andchenodeoxycholic acids, which are then conjugated to an amino acid (suchas glycine or taurine) to yield the conjugated form that is activelysecreted into cannaliculi. The most abundant of the bile salts in humansare cholate and deoxycholate, and they are normally conjugated witheither glycine or taurine to give glycocholate or taurocholaterespectively.

Free cholesterol is virtually insoluble in aqueous solutions, however inbile it is made soluble by the presence of bile acids and lipids.Hepatic synthesis of bile acids accounts for the majority of cholesterolbreakdown in the body. In humans, roughly 500 mg of cholesterol areconverted to bile acids and eliminated in bile every day. Therefore,secretion into bile is a major route for elimination of cholesterol.Large amounts of bile acids are secreted into the intestine every day,but only relatively small quantities are lost from the body. This isbecause approximately 95% of the bile acids delivered to the duodenumare absorbed back into blood within the ileum, by a process is known as“Enterohepatic Recirculation”.

Venous blood from the ileum goes straight into the portal vein, andhence through the sinusoids of the liver. Hepatocytes extract bile acidsvery efficiently from sinusoidal blood, and little escapes the healthyliver into systemic circulation. Bile acids are then transported acrossthe hepatocytes to be resecreted into canaliculi. The net effect of thisenterohepatic recirculation is that each bile salt molecule is reusedabout 20 times, often two or three times during a single digestivephase. Bile biosynthesis represents the major metabolic fate ofcholesterol, accounting for more than half of the approximate 800 mg/dayof cholesterol that an average adult uses up in metabolic processes. Incomparison, steroid hormone biosynthesis consumes only about 50 mg ofcholesterol per day. Much more that 400 mg of bile salts is required andsecreted into the intestine per day, and this is achieved by re-cyclingthe bile salts. Most of the bile salts secreted into the upper region ofthe small intestine are absorbed along with the dietary lipids that theyemulsified at the lower end of the small intestine. They are separatedfrom the dietary lipid and returned to the liver for re-use. Re-cyclingthus enables 20-30 g of bile salts to be secreted into the smallintestine each day.

Bile acids are amphipathic, with the cholesterol-derived portioncontaining both hydrophobic (lipid soluble) and polar (hydrophilic)moieties while the amino acid conjugate is generally polar andhydrophilic. This amphipathic nature enables bile acids to carry out twoimportant functions: emulsification of lipid aggregates andsolubilization and transport of lipids in an aqueous environment. Bileacids have detergent action on particles of dietary fat which causes fatglobules to break down or to be emulsified. Emulsification is importantsince it greatly increases the surface area of fat available fordigestion by lipases which cannot access the inside of lipid droplets.Furthermore, bile acids are lipid carriers and are able to solubilizemany lipids by forming micelles and are critical for transport andabsorption of the fat-soluble vitamins.

Pharmaceutical Compositions and Methods of Use

In some embodiments, compositions described herein are administered fordelivery of enteroendocrine peptide secretion enhancing agents to asubject or individual. In certain embodiments, any compositionsdescribed herein are formulated for ileal, rectal and/or colonicdelivery. In more specific embodiments, the composition is formulatedfor non-systemic or local delivery to the rectum and/or colon. It is tobe understood that as used herein, delivery to the colon includesdelivery to sigmoid colon, transverse colon, and/or ascending colon. Instill more specific embodiments, the composition is formulated fornon-systemic or local delivery to the rectum and/or colon isadministered rectally. In other specific embodiments, the composition isformulated for non-systemic or local delivery to the rectum and/or colonis administered orally.

In some embodiments, provided herein is a composition comprising anenteroendocrine peptide secretion enhancing agent and, optionally, apharmaceutically acceptable carrier for reducing food intake in anindividual. In some embodiments, provided herein is a compositioncomprising an enteroendocrine peptide secretion enhancing agent and,optionally, a pharmaceutically acceptable carrier for reducingcirculating glucose levels in an individual. In some embodiments,provided herein is a composition comprising an enteroendocrine peptidesecretion enhancing agent and, optionally, a pharmaceutically acceptablecarrier for increasing insulin levels in an individual. In specificembodiments, the composition is formulated for delivering theenteroendocrine peptide secretion enhancing agent to the distalgastrointestinal tract of the individual. Generally, a therapeuticallyeffective amount of an enteroendocrine peptide secretion enhancing agentis provided.

In certain embodiments, the composition comprises an enteroendocrinepeptide secretion enhancing agent and an absorption inhibitor. Inspecific embodiments, the absorption inhibitor is an inhibitor thatinhibits the absorption of the (or at least one of the) specificenteroendocrine peptide secretion enhancing agent with which it iscombined. In some embodiments, the composition comprises anenteroendocrine peptide secretion enhancing agent, an absorptioninhibitor and a carrier (e.g., an orally suitable carrier or a rectallysuitable carrier, depending on the mode of intended administration). Incertain embodiments, the composition comprises an enteroendocrinepeptide secretion enhancing agent, an absorption inhibitor, a carrier,and one or more of a cholesterol absorption inhibitor, anenteroendocrine peptide, a peptidase inhibitor, a spreading agent, and awetting agent.

In certain embodiments enteroendocrine peptide secretion enhancingagents are selected from, by way of non-limiting example, bile acids,bile acid mimic and/or modified bile acids. In more specificembodiments, compositions described herein are formulated fornon-systemic or local delivery of a bile acid, bile acid mimic and/ormodified bile acid (as the active component or components) to the rectumand/or colon, including the sigmoid colon, transverse colon, and/orascending colon. In certain embodiments, the compositions describedherein are administered rectally for non-systemic or local delivery ofthe bile acid active component to the rectum and/or colon, including thesigmoid colon, transverse colon, and/or ascending colon. In otherembodiments, the compositions described herein are administered orallyfor non-systemic delivery of the bile salt active component to therectum and/or colon, including the sigmoid colon, transverse colon,and/or ascending colon. In specific embodiments, compositions formulatedfor oral administration are, by way of non-limiting example, entericallycoated or formulated oral dosage forms, such as, tablets and/orcapsules. It is to be understood that the terms “subject” and“individual” are utilized interchangeably herein and include, e.g.,humans and human patients in need of treatment.

Enteroendocrine Peptide Enhancing Agents

In some embodiments, enteroendocrine peptide enhancing agents providedherein include, by way of non-limiting example, enteroendocrine peptidesecretion (e.g., of the L-cells) enhancing agents, inhibitors ofdegradation of enteroendocrine peptides (e.g., of the L-cells), orcombinations thereof.

In certain embodiments, the enteroendocrine peptide secretion enhancingagents used in the methods and compositions described herein include, byway of non-limiting example, a steroid acid or a nutrient. In specificembodiments, the steroid acid or nutrient described herein is a steroidacid or nutrient that enhances the secretion of an enteroendocrinepeptide. In specific embodiments, the steroid acid is an oxidizecholesterol acid. In some embodiments, an enteroendocrine peptidesecretion enhancing agent, bile acid, or bile acid mimic used in anycomposition or method described herein is a compound of Formula I:

In certain embodiments, each R¹ is independently H, OH, O-lower alkyl(e.g., OCH₃, or OEt). In some embodiments, each R¹ is independently H,OH, lower (e.g., C₁-C₆ or C₁-C₃) alkyl, or lower (e.g., C₁-C₆ or C₁-C₃)heteroalkyl. In certain embodiments, L is a substituted or unsubstitutedalkyl or substituted or unsubstituted heteroalkyl. In some embodiments,R² is H, OH, lower alkyl, or lower heteroalkyl (e.g., OMe). In certainembodiments, R³ is H, OH, G-lower alkyl, lower alkyl, or lowerheteroalkyl (e.g., OMe). In some embodiments, A is COOR⁴, S(O)_(n)R⁴, orOR⁵. In certain embodiments, R⁴ is H, an anion, a pharmaceuticallyacceptable cation (e.g., an alkali metal cation, alkaline earth metalcation, or any other pharmaceutically acceptable cation) substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an amino acid, or the like; and n is 1-3. Each R⁵ isindependently selected from lower alkyl and H.

In specific embodiments, L is unsubstituted branched or straight chainalkyl. In more specific embodiments, L is unsubstituted branched orstraight chain lower alkyl. In some embodiments, L is (CR⁵₂)_(m)—CONR⁵—(CR⁵ ₂)_(p). Each m is 1-6 and n is 1-6. In specificembodiments, m is 2 and n is 1. In other specific embodiments, m is 2and n is 2. In certain embodiments, A is COOH or COO—. In someembodiments, A is SO₃H or SO₃—.

In specific embodiments, the compound of Formula I has a structurerepresented by Figure (Ia):

In some embodiments, bile acid mimics include, by way of non-limitingexample,6-methyl-2-oxo-4-thiophen-2-yl-1,2,3,4-tetrahydro-phyrimidine-5-carboxylicacid benzyl ester (or TGR5-binding analogs thereof), oleanolic acid (orTGR5-binding analogs thereof), or the like.

In certain embodiments, enteroendocrine peptide secretion enhancingagents used in the methods and compositions described herein enhance thesecretion of an enteroendocrine peptide secreted by L-cells (e.g.,GLP-1, GLP-2, PYY, and the like). FIG. 1 (FIGS. 1A and 1B) illustratesthe response of enteroendocrine peptides to administration of bilesalts.

In some embodiments, the enteroendocrine peptide secretion enhancingagent is a steroid acid, such as a bile acid/salt, a bile acid/saltmimic, a modified bile acid/salt, or a combination thereof. The bileacids or salts thereof used in the methods and compositions describedherein include, by way of non-limiting example, cholic acid, deoxycholicacid, glycocholic acid, glycodeoxycholic acid, taurocholic acid,taurodihydrofusidate, taurodeoxycholic acid, cholate, glycocholate,deoxycholate, taurocholate, taurodeoxycholate, chenodeoxycholic acid,ursodeoxycholic acid and combinations thereof. In certain embodiments,bile salts used in the methods and compositions described herein arepharmaceutically acceptable salts including, by way of non-limitingexample, the sodium and potassium salts thereof. In specificembodiments, the enteroendocrine peptide secretion enhancing agent is apharmaceutically acceptable bile acid salt including, by way ofnon-limiting example, sodium glycocholate, sodium taurocholate andcombinations thereof. In some embodiments, more than one bile acidand/or salt is used in a methods and/or composition described herein. Incertain embodiments, the bile acid/salt used herein has a low orrelatively low solubility in water.

Although bile acids facilitate digestion and absorption of lipids in thesmall intestine, they are generally used in pharmaceutical formulationsas excipients. As excipients, bile acids find uses as surfactants and/oras agents that enhance the transfer of active components across mucosalmembranes, for systemic delivery of a pharmaceutically active compound.In certain embodiments of the methods and pharmaceutical compositionsdescribed herein, however, a bile acid, a bile acid mimic and/or amodified bile acid is the active agent used to enhance secretion ofenteroendocrine peptides.

In certain specific embodiments, the enteroendocrine peptide secretionenhancing agents used in the methods and compositions described hereinare modified bile acids/salts. In certain embodiments, the bileacid/salt is modified in such a way so as to inhibit absorption of thebile acid/salt across the rectal or colonic mucosa.

In certain embodiments, the enteroendocrine peptide secretion enhancingagents described herein are a glucogen-like peptide secretion enhancingagent. In a specific embodiment, the glucugen-like peptide secretionenhancing agent is a bile acid, a bile acid mimic or a modified bileacid. In some embodiments, the glucogen-like peptide secretion enhancingagents are selected from, by way of non-limiting example, glucogen-likepeptide-1 (GLP-1) secretion enhancing agents or glucogen-like peptide-2(GLP-2) secretion enhancing agents. In some embodiments, theglucogen-like peptide secretion enhancing agents enhance both GLP-1 andGLP-2. In a specific embodiment, the GLP-1 and/or GLP-2 secretionenhancing agent is selected from bile acids, bile acid mimics ormodified bile acids.

In certain embodiments, the enteroendocrine peptide secretion enhancingagent described herein is a pancreatic polypeptide-fold peptidesecretion enhancing agent. In more specific embodiments, the pancreaticpolypeptide-fold peptide secretion enhancing agent is selected from, byway of non-limiting example, peptide YY (PYY) secretion enhancingagents. In specific embodiments, the pancreatic polypeptide-fold peptidesecretion enhancing agent or the PYY secretion enhancing agent isselected from a bile acid, a bile acid mimic, a modified bile acid or afatty acid or salt thereof (e.g., a short chain fatty acid).

In some embodiments, the enteroendocrine peptide secretion enhancingagent is selected from, by way of non-limiting example, carbohydrates,glucose, fats, and proteins. In certain embodiments, the enteroendocrinepeptide secretion enhancing agent is selected from fatty acids,including long chain fatty acids and short chain fatty acids. Shortchain fatty acids and salts include, by way of non-limiting example,propionic acid, butyric acid, propionate, and butyrate.

In some embodiments, the enteroendocrine peptide secretion enhancingagent is selected from, by way of non-limiting example, carbohydrates,glucose, fat, protein, protein hydrolysate, amino acids, nutrients,intestinal peptides, peripheral hormones that participate in energyhomeostasis, such as the adipocyte hormone leptin, bile acids/salts,insulin, gastrin-releasing peptide (GRP), gut peptides, gastric acid,CCK, insulin-like growth factor 1, bombesin, calcitonin-gene-relatedpeptide and combinations thereof that enhance the secretion ofenteroendocrine peptides.

In certain embodiments, the inhibitors of degradation of L-cellenteroendocrine peptide products include DPP-IV inhibitors, TGR5modulators (e.g., TGR5 agonists), or combinations thereof. In certaininstances, the administration of a DPP-IV inhibitor in combination withany of the compounds disclosed herein reduces or inhibits degradation ofGLP-1 or GLP-2. In certain instances, administration of a TGR5 agonistin combination with any of the compounds disclosed herein enhances thesecretion of enteroendocrine peptide products from L-cells. In someinstances, the enteroendocrine peptide enhancing agent agonizes orpartially agonizes bile acid receptors (e.g., TGR5 receptors orFarnesoid-X receptors) on in the gastrointestinal tract.

DPP-IV inhibitors include(2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile(vildagliptin),(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (sitagliptin),(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(saxagliptin), and2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile(alogliptin). TGR5 modulators (e.g., agonists) include the compoundsdisclosed in, e.g, WO2008/091540, WO 2008067219 and US Appl. No.2008/0221161, the TGR5 modulators (e.g., agonists) of which are herebyincorporated herein by reference.

FIG. 2 illustrates the affect on food intake of pump infusion of TCA inconcentrations of 150 mM and 500 mM. FIG. 3 illustrates the affect onbody weight of pump infusion of TCA in concentrations of 150 mM and 500mM.

Absorption Inhibitors

In certain embodiments, the compositions described herein are and themethods described herein include administering a composition that isformulated for the non-systemic delivery of enteroendocrine peptidesecretion enhancing agents to the rectum and/or colon (sigmoid,transverse, and/or ascending colon). As previously discussed,enteroendocrine peptide secretion enhancing agents include, by way ofnon-limiting example, bile acids, bile salts, bile acid mimics, bilesalt mimics, modified bile acids, modified bile salts and combinationsthereof. In certain embodiments, the composition described herein asbeing formulated for the non-systemic delivery of enteroendocrinepeptide secretion enhancing agents further includes an absorptioninhibitor. As used herein, an absorption inhibitor includes an agent orgroup of agents that inhibit absorption of the enteroendocrine peptidesecretion enhancing agent across the rectal or colonic mucosa. Inspecific embodiments, the absorption inhibitor is an absorptioninhibitor that inhibits the absorption of the specific enteroendocrinepeptide secretion enhancing agent with which it is combined.

Suitable bile acid absorption inhibitors (also described herein asabsorption inhibiting agents) include, by way of non-limiting example,anionic exchange matrices, polyamines, quaternary amine containingpolymers, quaternary ammonium salts, polyallylamine polymers andcopolymers, colesevelam, colesevelam hydrochloride, CholestaGel(N,N,N-trimethyl-6-(2-propenylamino)-1-hexanaminium chloride polymerwith (chloromethyl)oxirane, 2-propen-1-amine andN-2-propenyl-1-decanamine hydrochloride), cyclodextrins, chitosan,chitosan derivatives, carbohydrates which bind bile acids, lipids whichbind bile acids, proteins and proteinaceous materials which bind bileacids, and antibodies and albumins which bind bile acids. Suitablecyclodextrins include those that bind bile acids such as, by way ofnon-limiting example, β-cyclodextrin and hydroxypropyl-β-cyclodextrin.Suitable proteins, include those that bind bile acids such as, by way ofnon-limiting example, bovine serum albumin, egg albumin, casein, α¹-acidglycoprotein, gelatin, soy proteins, peanut proteins, almond proteins,and wheat vegetable proteins.

In certain embodiments the absorption inhibitor is cholestyramine. Inspecific embodiments, cholestyramine is combined with a bile acid.Cholestyramine, an ion exchange resin, is a styrene polymer containingquaternary ammonium groups crosslinked by divinylbenzene. In otherembodiments, the absorption inhibitor is colestipol. In specificembodiments, colestipol is combined with a bile acid. Colestipol, an ionexchange resin, is a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane.

In certain embodiments of the compositions and methods described hereinthe enteroendocrine peptide secretion enhancing agent is linked to anabsorption inhibitor, while in other embodiments the enteroendocrinepeptide secretion enhancing agent and the absorption inhibitor areseparate molecular entities. In specific embodiments the bile acid, bileacid mimic or the modified bile acid is linked to a bile acid adsorptioninhibitor described herein.

Cholesterol Absorption Inhibitors

In certain embodiments, a composition described herein optionallyincludes at least one cholesterol absorption inhibitor. Suitablecholesterol absorption inhibitors include, by way of non-limitingexample, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors,stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholineanalogues, β-lactam cholesterol absorption inhibitors, sulfatepolysaccharides, neomycin, plant sponins, plant sterols, phytostanolpreparation FM-VP4, Sitostanol, β-sitosterol,acyl-CoA:cholesterol-O-acyltransferase (ACAT) inhibitors, Avasimibe,Implitapide, steroidal glycosides and the like. Suitable enzetimibeanalogs include, by way of non-limiting example, SCH 48461, SCH 58053and the like. Suitable ACT inhibitors include, by way of non-limitingexample, trimethoxy fatty acid anilides such as CI-976, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide,melinamide and the like. β-lactam cholesterol absorption inhibitorsinclude, by way of non-limiting example,(3R-4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone andthe like.

Enteroendocrine Peptides

In certain embodiments, the compositions described herein optionallyinclude at least one enteroendocrine peptide. Suitable enteroendocrinepeptides include, by way of non-limiting example, glucogen-like peptidesGLP-1 and/or GLP-2, or pancreatic polypeptide-fold peptides pancreaticpolypeptide (PP), neuropeptide Y (NPY) and/or peptide YY (PYY).

Peptidase Inhibitors

In some embodiments, the compositions described herein optionallyinclude at least one peptidase inhibitor. Such peptidase inhibitorsinclude, but are not limited to, dipeptidyl peptidase-4 inhibitors(DPP-4), neutral endopeptidase inhibitors, and converting enzymeinhibitors. Suitable dipeptidyl peptidase-4 inhibitors (DPP-4) include,by way of non-limiting example, Vildaglipti,2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile,Sitagliptin,(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,Saxagliptin, and(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile.Such neutral endopeptidase inhibitors include, but are not limited to,Candoxatrilat and Ecadotril.

Spreading Agents/Wetting Agents

In certain embodiments, the composition described herein optionallycomprises a spreading agent. In some embodiments, a spreading agent isutilized to improve spreading of the composition in the colon and/orrectum. Suitable spreading agents include, by way of non-limitingexample, hydroxyethylcellulose, hydroxypropymethyl cellulose,polyethylene glycol, colloidal silicon dioxide, propylene glycol,cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone,polyoxyethylated glycerides, polycarbophil, di-n-octyl ethers, Cetiol™OE, fatty alcohol polyalkylene glycol ethers, Aethoxal™ B), 2-ethylhexylpalmitate, Cegesoft™ C 24), and isopropyl fatty acid esters.

In some embodiments, the compositions described herein optionallycomprise a wetting agent. In some embodiments, a wetting agent isutilized to improve wettability of the composition in the colon andrectum. Suitable wetting agents include, by way of non-limiting example,surfactants. In some embodiments, surfactants are selected from, by wayof non-limiting example, polysorbate (e.g., 20 or 80), stearylhetanoate, caprylic/capric fatty acid esters of saturated fatty alcoholsof chain length C₁₂-C₁₈, isostearyl diglycerol isostearic acid, sodiumdodecyl sulphate, isopropyl myristate, isopropyl palmitate, andisopropyl myristate/isopropyl stearate/isopropyl palmitate mixture.

Methods

In certain embodiments, provided herein is a method of treating ametabolic disease or a condition associated with a metabolic diseasewith an enteroendocrine peptide secretion enhancing agent and anoptional carrier. In some embodiments, provided herein are methods oftreating a metabolic disease comprising administering any composition asdescribed herein. In some embodiments, provided herein is the use of anyof the pharmaceutical compositions described herein in preparing amedicament for treating a metabolic disease. In specific embodiments,the metabolic disease is selected from, by way of non-limiting example,obesity, diabetes, and a combination thereof. In some embodiments,provided herein is a method of treating a condition associated with ametabolic disease. In certain embodiments, provided herein is the use ofany of the pharmaceutical compositions described herein in preparing amedicament for treating a condition associated with a metabolic disease.In some embodiments, conditions associated with a metabolic disease areselected from, by way of non-limiting example, weight gain, food intake,appetite, impaired glucose tolerance, a glucose metabolic disorder, andinsulin resistance. In certain embodiments, conditions associated with ametabolic disease are selected from, by way of non-limiting example,acute coronary syndrome, hibernating myocardium, ventriculardysfunction, cardiac risk, post myocardial infarction mortality,post-surgical catabolism, sepsis-related catabolism, criticalillness-related catabolism, post-surgical mortality, sepsis-relatedmortality, critical illness-related mortality, criticalillness-polyneuropathy, congestive heart failure, toxic hypervolemia,renal failure, ischemia-reperfusion injury, mortality and morbitity fromstroke, mortality and morbitity from neurodegenerative disease,neuropathy, inflammatory bowel disease, bowel mucosal injury, impairedbowel integrity, irritable bowel disease, osteopenia, and a bonefracture or a bone disorder. It is to be understood that the term,“treating” includes controlling, suppressing, inhibiting, reducing thesymptoms of and/or preventing.

Furthermore, in certain embodiments, provided herein is a method ofdecreasing appetite, decreasing food intake, and/or decreasing appetiteby administering a therapeutically effective amount of anyenteroendocrine peptide secretion enhancing agent or compositiondescribed herein. In some embodiments, provided herein is anenteroendocrine peptide secretion enhancing agent or a composition usedfor preparing a medicament for decreasing appetite, decreasing foodintake, and/or decreasing appetite.

In some embodiments, provided herein is a method of treating obesity ordiabetes in an individual comprising delivering to ileal, colon, and/orrectal L-cells of the individual a therapeutically effective amount ofany enteroendocrine peptide secretion enhancing agent described herein.In certain embodiments, the therapeutically effective amount ofenteroendocrine peptide secretion enhancing agent stimulates oractivates the L-cells to which the enteroendocrine peptide secretionenhancing agent is administered.

FIG. 11 illustrates the reduction of food intake in response toadministration of anenteroendocrine peptide secretion enhancing agent.FIG. 11 illustrates that with increased amounts of enteroendocrinepeptide secretion enhancing agent administered to the distalgastrointestinal tract, decreased amounts of calories were consumed byhuman subjects.

In some embodiments, provided herein is a method of treating diabetes inan individual comprising delivering to ileal, colon, and/or rectalL-cells of an individual in need thereof a therapeutically effectiveamount of any enteroendocrine peptide secretion enhancing agentdescribed herein. In certain embodiments, provided herein is a method oftreating diabetes in an individual comprising delivering to ileum,colon, and/or rectum of an individual in need thereof a therapeuticallyeffective amount of any enteroendocrine peptide secretion enhancingagent described herein. In some embodiments, provided herein is a methodof elevating insulin levels in an individual comprising delivering toileum, colon, and/or rectum of an individual in need thereof (e.g., adiabetic individual) a therapeutically effective amount of anyenteroendocrine peptide secretion enhancing agent described herein. Incertain embodiments, provided herein is a method of reducing glucoselevels in an individual comprising delivering to ileum, colon, and/orrectum of an individual in need thereof (e.g., a diabetic individual) atherapeutically effective amount of any enteroendocrine peptidesecretion enhancing agent described herein. In some embodiments, thetherapeutically effective amount of enteroendocrine peptide secretionenhancing agent stimulates or activates the L-cells of the ileum, colon,and/or rectum to which the enteroendocrine peptide secretion enhancingagent is administered.

FIG. 12 illustrates the insulin response to administration of anenteroendocrine peptide secretion enhancing agent. FIG. 12 illustratesthat with increased amounts of enteroendocrine peptide secretionenhancing agent administered to the distal gastrointestinal tract, humandiabetics demonstrated increased levels of insulin. FIG. 13 illustratesthe incremental integrated response of insulin levels to administrationof an enteroendocrine peptide secretion enhancing agent.

FIG. 14 illustrates the glucose response to administration ofanenteroendocrine peptide secretion enhancing agent. FIG. 14 illustratesthat with increased amounts of enteroendocrine peptide secretionenhancing agent administered to the distal gastrointestinal tract, humandiabetics demonstrated decreased levels of glucose. FIG. 15 illustratesthe incremental integrated response of glucose levels to administrationof an enteroendocrine peptide secretion enhancing agent.

In some embodiments, provided herein is a method of elevating GLP-1,PYY, oxyntomodulin, insulin, or a combination thereof levels in anindividual comprising delivering to ileum, colon, and/or rectum of anindividual in need thereof (e.g., a diabetic individual) atherapeutically effective amount of any enteroendocrine peptidesecretion enhancing agent described herein. In some embodiments,provided herein is a method of elevating GLP-1, PYY, oxyntomodulin, andinsulin levels in an individual comprising delivering to ileum, colon,and/or rectum of an individual in need thereof (e.g., a diabeticindividual) a therapeutically effective amount of any enteroendocrinepeptide secretion enhancing agent described herein.

In certain embodiments, the pharmaceutical composition administeredincludes a therapeutically effective amount of an enteroendocrinepeptide secretion enhancing agent, an absorption inhibitor and a carrier(e.g., an orally suitable carrier or a rectally suitable carrier,depending on the mode of intended administration). In certainembodiments, the pharmaceutical composition used or administeredcomprises an enteroendocrine peptide secretion enhancing agent, anabsorption inhibitor, a carrier, and one or more of a cholesterolabsorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor,a spreading agent, and a wetting agent.

In a specific embodiment, the pharmaceutical composition used to preparea rectal dosage form or administered rectally comprises anenteroendocrine peptide secretion enhancing agent, an absorptioninhibitor, a rectally suitable carrier, an optional cholesterolabsorption inhibitor, an optional enteroendocrine peptide, an optionalpeptidase inhibitor, an optional spreading agent, and an optionalwetting agent. In certain embodiments, rectally administeredcompositions evokes an anorectal response. In specific embodiments, theanorectal response is an increase in secretion of one or moreenteroendocrine by cells (e.g., L-cells) in the colon and/or rectum(e.g., in the epithelial layer of the colon and/or rectum). In someembodiments, the anorectal response persists for at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24hours. In other embodiments the anorectal response persists for a periodbetween 24 hours and 48 hours, while in other embodiments the anorectalresponse persists for persists for a period greater than 48 hours.

In another specific embodiment, the pharmaceutical composition used toprepare an oral dosage form or administered orally comprises anenteroendocrine peptide secretion enhancing agent, an absorptioninhibitor, an orally suitable carrier, an optional cholesterolabsorption inhibitor, an optional enteroendocrine peptide, an optionalpeptidase inhibitor, an optional spreading agent, and an optionalwetting agent. In certain embodiments, the orally administeredcompositions evokes an anorectal response. In specific embodiments, theanorectal response is an increase in secretion of one or moreenteroendocrine by cells in the colon and/or rectum (e.g., in L-cellsthe epithelial layer of the colon and/or rectum). In some embodiments,the anorectal response persists for at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. Inother embodiments the anorectal response persists for a period between24 hours and 48 hours, while in other embodiments the anorectal responsepersists for persists for a period greater than 48 hours.

Provided herein are methods for prevention and/or treatment ofcongestive heart failure, ventricular dysfunction, toxic hypervolemia,polycystic ovary syndrome, inflammatory bowel disease, impaired bowelintegrity, short bowel syndrome, gastritis, peptic ulcer, or irritablebowel disease comprising contacting the distal gastrointestinal tract(e.g., colon and/or rectum) of an individual in need thereof with anenteroendocrine peptide secretion enhancing agent and an optionalabsorption inhibitor. In some embodiments, the methods further compriseadministration of a DPP-IV inhibitor, a TGR5 agonist, a biguanide, anincretin mimetic, or GLP-1 or an analog thereof. Provided herein aremethods for prevention and/or treatment of radiation enteritiscomprising contacting the distal gastrointestinal tract (e.g., colonand/or rectum) of an individual in need thereof with an enteroendocrinepeptide secretion enhancing agent and an optional absorption inhibitor.In some embodiments, the methods further comprise administration of aDPP-IV inhibitor, a TGR5 agonist, a biguanide, an incretin mimetic, orGLP-1 or an analog thereof. Provided in certain embodiments herein is amethod of promoting regeneration of the gastrointestinal tract byadministering to the distal gastrointestinal tract (e.g., colon and/orrectum) of the individual, a therapeutically effective amount of anenteroendocrine peptide secretion enhancing agent and an optionalabsorption inhibitor. In some embodiments, the methods further compriseadministration of a DPP-IV inhibitor, a TGR5 agonist, a biguanide, anincretin mimetic, or GLP-2 or an analog thereof. In some instances,radiation enteritis, or an inflammation of the intestine, is not onlymajor complication of cancer radiation therapy, but occur after anyaccidental and intentional radiation exposure. In certain instances,GLP-2 secreted from L-cells (e.g., by administration thereto anenteroendocrine peptide secretion enhancing agent described herein)plays important role in regeneration of GI tract injuries.

Routes of Administration and Dosage

In some embodiments, the compositions described herein and thecompositions administered in the methods described herein are formulatedto enhance enteroendocrine peptide secretion and to evoke an anorectalresponse. In certain embodiments, the compositions described herein areformulated for rectal or oral administration. In some embodiments, suchformulations are administered rectally or orally, respectively. In someembodiments, the compositions described herein are combined with adevice for local delivery of the compositions to the rectum and/or colon(sigmoid colon, transverse colon, or ascending colon). In certainembodiments, for rectal administration the composition described hereinare formulated as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas. In someembodiments, for oral administration the compositions described hereinare formulated for oral administration and enteric delivery to thecolon.

In certain embodiments, the compositions or methods described herein arenon-systemic. In some embodiments, compositions described herein deliverthe enteroendocrine peptide secretion enhancing agent to the distalileum, colon, and/or rectum and not systemically (e.g., a substantialportion of the enteroendocrine peptide secretion enhancing agent is notsystemically absorbed). In some embodiments, oral compositions describedherein deliver the enteroendocrine peptide secretion enhancing agent tothe distal ileum, colon, and/or rectum and not systemically (e.g., asubstantial portion of the enteroendocrine peptide secretion enhancingagent is not systemically absorbed). In some embodiments, rectalcompositions described herein deliver the enteroendocrine peptidesecretion enhancing agent to the distal ileum, colon, and/or rectum andnot systemically (e.g., a substantial portion of the enteroendocrinepeptide secretion enhancing agent is not systemically absorbed). Incertain embodiments, non-systemic compositions described herein deliverless than 90% w/w of the enteroendocrine peptide secretion enhancingagent systemically. In certain embodiments, non-systemic compositionsdescribed herein deliver less than 80% w/w of the enteroendocrinepeptide secretion enhancing agent systemically. In certain embodiments,non-systemic compositions described herein deliver less than 70% w/w ofthe enteroendocrine peptide secretion enhancing agent systemically. Incertain embodiments, non-systemic compositions described herein deliverless than 60% w/w of the enteroendocrine peptide secretion enhancingagent systemically. In certain embodiments, non-systemic compositionsdescribed herein deliver less than 50% w/w of the enteroendocrinepeptide secretion enhancing agent systemically. In certain embodiments,non-systemic compositions described herein deliver less than 40% w/w ofthe enteroendocrine peptide secretion enhancing agent systemically. Incertain embodiments, non-systemic compositions described herein deliverless than 30% w/w of the enteroendocrine peptide secretion enhancingagent systemically. In certain embodiments, non-systemic compositionsdescribed herein deliver less than 25% w/w of the enteroendocrinepeptide secretion enhancing agent systemically. In certain embodiments,non-systemic compositions described herein deliver less than 20% w/w ofthe enteroendocrine peptide secretion enhancing agent systemically. Incertain embodiments, non-systemic compositions described herein deliverless than 15% w/w of the enteroendocrine peptide secretion enhancingagent systemically. In certain embodiments, non-systemic compositionsdescribed herein deliver less than 10% w/w of the enteroendocrinepeptide secretion enhancing agent systemically. In certain embodiments,non-systemic compositions described herein deliver less than 5% w/w ofthe enteroendocrine peptide secretion enhancing agent systemically. Insome embodiments, systemic absorption is determined in any suitablemanner, including the total circulating amount, the amount cleared afteradministration, or the like.

In certain embodiments, the compositions and/or formulations describedherein are administered at least once a day. In certain embodiments, theformulations containing the enteroendocrine peptide secretion enhancingagents are administered at least twice a day, while in other embodimentsthe formulations containing the enteroendocrine peptide secretionenhancing agents are administered at least three times a day. In certainembodiments, the formulations containing the enteroendocrine peptidesecretion enhancing agents are administered up to five times a day. Itis to be understood that in certain embodiments, the dosage regimen ofcomposition containing the enteroendocrine peptide secretion enhancingagents described herein to is determined by considering various factorssuch as the patient's age, sex, and diet.

The concentration of the enteroendocrine peptide secretion enhancingagents administered in the formulations described herein ranges fromabout 1 mM to about 1 M. In certain embodiments the concentration of theenteroendocrine peptide secretion enhancing agents administered in theformulations described herein ranges from about 1 mM to about 750 mM. Incertain embodiments the concentration of the enteroendocrine peptidesecretion enhancing agents administered in the formulations describedherein ranges from about 1 mM to about 500 mM. In certain embodimentsthe concentration of the enteroendocrine peptide secretion enhancingagents administered in the formulations described herein ranges fromabout 5 mM to about 500 mM. In certain embodiments the concentration ofthe enteroendocrine peptide secretion enhancing agents administered inthe formulations described herein ranges from about 10 mM to about 500mM. In certain embodiments the concentration of the enteroendocrinepeptide secretion enhancing agents administered in the formulationsdescribed herein ranges from about 25 mM to about 500 mM. In certainembodiments the concentration of the enteroendocrine peptide secretionenhancing agents administered in the formulations described hereinranges from about 50 mM to about 500 mM. In certain embodiments theconcentration of the enteroendocrine peptide secretion enhancing agentsadministered in the formulations described herein ranges from about 100mM to about 500 mM. In certain embodiments the concentration of theenteroendocrine peptide secretion enhancing agents administered in theformulations described herein ranges from about 200 mM to about 500 mM.

In certain embodiments, any composition described herein comprises atherapeutically effective amount (e.g., to treat obesity and/ordiabetes) of an enteroendocrine peptide secretion enhancing agent (e.g.,bile acid). In some embodiments, compositions described herein compriseor methods described herein comprise administering about 0.01 mg toabout 10 g of an enteroendocrine peptide secretion enhancing agent(e.g., bile acid). In certain embodiments, a composition describedherein comprises or a method described herein comprises administeringabout 0.1 mg to about 500 mg of an enteroendocrine peptide secretionenhancing agent (e.g., bile acid). In certain embodiments, a compositiondescribed herein comprises or a method described herein comprisesadministering about 0.1 mg to about 100 mg of an enteroendocrine peptidesecretion enhancing agent (e.g., bile acid). In certain embodiments, acomposition described herein comprises or a method described hereincomprises administering about 0.1 mg to about 50 mg of anenteroendocrine peptide secretion enhancing agent (e.g., bile acid). Incertain embodiments, a composition described herein comprises or amethod described herein comprises administering about 0.1 mg to about 10mg of an enteroendocrine peptide secretion enhancing agent (e.g., bileacid). In certain embodiments, a composition described herein comprisesor a method described herein comprises administering about 0.5 mg toabout 10 mg of an enteroendocrine peptide secretion enhancing agent(e.g., bile acid). In some embodiments, compositions described hereincomprise or methods described herein comprise administering about 0.1mmol to about 1 mol of an enteroendocrine peptide secretion enhancingagent (e.g., bile acid). In certain embodiments, a composition describedherein comprises or a method described herein comprises administeringabout 0.01 mmol to about 500 mmol of an enteroendocrine peptidesecretion enhancing agent (e.g., bile acid). In certain embodiments, acomposition described herein comprises or a method described hereincomprises administering about 0.1 mmol to about 100 mmol of anenteroendocrine peptide secretion enhancing agent (e.g., bile acid). Incertain embodiments, a composition described herein comprises or amethod described herein comprises administering about 0.5 mmol to about30 mmol of an enteroendocrine peptide secretion enhancing agent (e.g.,bile acid). In certain embodiments, a composition described hereincomprises or a method described herein comprises administering about 0.5mmol to about 20 mmol of an enteroendocrine peptide secretion enhancingagent (e.g., bile acid). In certain embodiments, a composition describedherein comprises or a method described herein comprises administeringabout 1 mmol to about 10 mmol of an enteroendocrine peptide secretionenhancing agent (e.g., bile acid). In certain embodiments, a compositiondescribed herein comprises or a method described herein comprisesadministering about 0.01 mmol to about 5 mmol of an enteroendocrinepeptide secretion enhancing agent (e.g., bile acid). In certainembodiments, a composition described herein comprises or a methoddescribed herein comprises administering about 0.1 mmol to about 1 mmolof an enteroendocrine peptide secretion enhancing agent (e.g., bileacid). In various embodiments, certain enteroendocrine peptide secretionenhancing agents (e.g., bile acids) have different potencies and dosingis optionally adjusted accordingly. For example, the investigation inTGR5-transfected CHO cells of TGR5 agonist potency of natural bile acidsindicates the following rank of potency: Lithocholic acid(LCA)>deoxycholic acid (DCA)>murocholic acid (Muro-CA)>lagodeoxycholicacid (lago-DCA)>chenodeoxycholic (CDCA)>cholic acid (CA)>hyodeoxycholicacid (HDCA>ursodeoxycholic acid (UDCA); and assays on TGR5-transfectedCHO cells demonstrate that EC₅₀ (in μM) for UDCA was 36.4, TauroCA (TCA)4.95 and LCA 0.58.

In certain embodiments, by targeting the distal gastrointestinal tract(e.g., distal ileum, colon, and/or rectum), compositions and methodsdescribed herein provide efficacy (e.g., in reducing food intake,treating obesity, treating diabetes) with a reduced dose ofenteroendocrine peptide secretion enhancing agent (e.g., as compared toan oral dose that does not target the distal gastrointestinal tract).

Rectal Administration Formulations

The pharmaceutical compositions described herein for the non-systemicdelivery of enteroendocrine peptide secretion enhancing agents to therectum and/or colon are formulated for rectal administration as rectalenemas, rectal foams, rectal gels, and rectal suppositories. Thecomponents of such formulations are described herein. It is to beunderstood that as used herein, pharmaceutical compositions andcompositions are or comprise the formulations as described herein.

Rectal Enemas

In certain embodiments, the compositions described herein are formulatedas rectal enema formulations for non-systemic delivery ofenteroendocrine peptide secretion enhancing agents. In certainembodiments, such rectal enemas are formulated as a solution, aqueoussuspension or emulsion. In some embodiments, solution enemas contain acarrier vehicle, an enteroendocrine peptide secretion enhancing agent,an absorption inhibitor (e.g., of the enteroendocrine peptide secretionenhancing agent across the rectal or colonic mucosa), and one or more ofthe following: a solubilizer, a preservative, a chelating agent, abuffer for pH regulation, and a thickener. In certain embodiments,rectal enemas are formulated as an emulsion or aqueous suspensioncontaining a carrier vehicle, at least one enteroendocrine peptidesecretion enhancing agent, at least one agent for inhibiting absorptionof the enteroendocrine peptide secretion enhancing agent across therectal or colonic mucosa, and one or more of the following: apreservative, a chelating agent, a buffer for pH regulation, asolubilizer, a thickener, and an emulsifier/surfactant.

In certain embodiments, rectal enemas are formulated such that aenteroendocrine peptide secretion enhancing agent is dissolved ordispersed in a suitable flowable carrier vehicle, including but notlimited to water, alcohol or an aqueous-alcoholic mixture. In certainembodiments, the carrier vehicle is thickened with natural or syntheticthickeners. In further embodiments the rectal enema formulations alsocontain a lubricant.

In some embodiments, unit dosages of such enema formulations areadministered from prefilled bags or syringes.

In certain embodiments, the volume of enema administered using suchrectal enema formulations is a volume suitable for achieving a desiredresult, e.g., from about 10 mL to about 1000 mL. In certain embodiments,the volume of enema administered using such rectal enema formulations isfrom about 10 mL to about 900 mL. In certain embodiments, the volume ofenema administered using such rectal enema formulations is from about 10mL to about 800 mL. In certain embodiments, the volume of enemaadministered using such rectal enema formulations is from about 10 mL toabout 700 mL. In certain embodiments, the volume of enema administeredusing such rectal enema formulations is from about 10 mL to about 600mL. In certain embodiments, the volume of enema administered using suchrectal enema formulations is from about 10 mL to about 500 mL. Incertain embodiments, the volume of enema administered using such rectalenema formulations is from about 10 mL to about 400 mL. In certainembodiments, the volume of enema administered using such rectal enemaformulations is from about 10 mL to about 300 mL. In certainembodiments, the volume of enema administered using such rectal enemaformulations is from about 10 mL to about 200 mL. In certainembodiments, the volume of enema administered using such rectal enemaformulations is from about 10 mL to about 100 mL.

Rectal Foams

In certain instances, leakage is a problem associated with enemas. Assuch, it is often desirable or necessary for patients to lie down duringadministration of enemas. In some embodiments, rectal administrationusing foams overcomes the problem of leakage from the rectum followingadministration.

In certain embodiments, the pharmaceutical compositions are formulatedas rectal foams. In some embodiments, rectal foams are used for therectal administration and for local or non-systemic delivery ofenteroendocrine peptide secretion enhancing agents to the rectum and/orcolon. Such rectal foams formulations contain an enteroendocrine peptidesecretion enhancing agent dissolved or suspended in a liquid carriervehicle, an absorption inhibitor (e.g., of the enteroendocrine peptidesecretion enhancing agent across the rectal or colonic mucosa), asurfactant/emulsifier with foaming properties and a propellant (e.g., apropellant gas). In certain embodiments, rectal foam formulations alsocontain one or more of the following: a suspending/solubilizing agent, athickener, a preservative, a chelating agent, a buffer, an antioxidant,a tonicity modifiers, and a spreading agent. In certain embodiments,surfactants/emulsifiers include, by way of non-limiting example,non-ionic surfactants, anionic surfactants, cationic surfactants, andcombinations thereof.

In certain embodiments, rectal foam formulations are filled inpressurized containers prior to rectal administration. In certainembodiments the pressurized container is a can. In certain embodiments,propellants used herein include, by way of non-limiting example,hydrocarbons (such as isobutane, N-butane or propane), fluorocarbons(e.g. dichlorodifluoromethane and dichlorotetrafluoroethane),chlorofluorocarbons, dimethyl ether, hydrofluorocarbons, compressedgases, freon (such as freon 12, freon 114), hydrochlorofluorocarbons,hydrofluorocarbons or mixtures thereof.

In some embodiments, the maximum amount of propellant used is determinedby its miscibility with other components in the composition to form amixture, such as a homogeneous mixture. In certain embodiments, theminimal level of propellant used in the composition is determined by thedesired foam characteristics, and its ability to substantially orcompletely evacuate the container.

In some embodiments, the propellant concentration used in such rectalfoam formulations is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 50%,55% to about 60% (w/w).

In certain embodiments, rectal foams are formed upon rectaladministration, wherein the dispensing valve of the can allows rapidexpansion of the propellant, triggering the foaming action of thesurfactant and resulting foam forms within the rectum and colon. Inother embodiments, the rectal foams used for rectal administration ofthe compositions described herein are formed within the dispensingcontainer prior to rectal administration.

The distance the foam can reach within the colon and rectum iscontrolled by controlling the foam propelling properties by varying thetype and quantity of propellant used. The volume of foam administeredusing such rectal foam formulations is from about 10 mL to about 1000mL. In certain embodiments, the volume of a composition described herein(e.g., a foam) described herein or used in a method described herein(e.g., a foam, enema, or gel) is from about 10 mL to about 900 mL. Incertain embodiments, the volume of a composition described herein (e.g.,a foam) described herein or used in a method described herein (e.g., afoam, enema, or gel) is from about 10 mL to about 800 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 700 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 600 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 500 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 400 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 300 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 200 mL. In certainembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is from about 10 mL to about 100 mL. In specificembodiments, the volume of a composition described herein (e.g., a foam)described herein or used in a method described herein (e.g., a foam,enema, or gel) is about 20 mL to about 60 mL, about 20 mL, about 40 mL,or about 60 mL.

Rectal Gels

In some embodiments, the pharmaceutical compositions described hereinare formulated as rectal gels. In certain embodiments, the rectal gelsare suitable for the regional or local non-systemic administration ofone or more enteroendocrine peptide secretion enhancing agents to therectum and/or colon. In some embodiments, rectal gel formulationscontain at least one enteroendocrine peptide secretion enhancing agentdissolved or suspended in a solvent/liquid carrier vehicle, anabsorption inhibitor (e.g., of the enteroendocrine peptide secretionenhancing agent across the rectal or colonic mucosa) and at least onethickening agents. In certain embodiments such rectal gel formulationsalso contain one or more of the following: a buffering agent(s), apreservative(s), and an antioxidant(s).

In certain embodiments, rectal gels have gel-like consistencies but aresufficiently flowable so as to be capable of local or regionaladministration through a catheter, needle, syringe, or other comparablemeans of local or regional administration.

In some embodiments, the concentration of a thickener used in a rectalgel formulation is in an amount or concentration suitable to achieve adesired thickness or viscosity, e.g., from about 0.05% to about 10% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 8% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 7% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 6% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 5% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 4% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 3% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 2% byweight. In certain embodiments, the concentration of the thickener usedin such rectal gel formulations ranges from about 0.05% to about 1% byweight. In certain embodiments the rectal gel formualtion includesmethyl cellulose having a concentration from about 0.05% to about 2%,while in other embodiments the rectal gel formualtion includes methylcellulose having a concentration of about 1%.

In some embodiments, the any formulation described herein (e.g., arectalgel formulation) has a viscosity ranging from about 500 to about 50,000centipoise (cP) at 25 C. In certain embodiments, the viscosity of theformulation described herein is from about 500 to about 40,000centipoise (cP) at 25 C. In certain embodiments, the viscosity of theformulation described herein is from about 500 to about 30,000centipoise (cP) at 25 C. In certain embodiments, the viscosity of theformulation described herein is from about 500 to about 20,000centipoise (cP) at 25 C. In certain embodiments, the viscosity of theformulation described herein is from about 500 to about 10,000centipoise (cP) at 25 C. In some embodiments, the formulation has afinal viscosity of less than about 40,000 centipoises (cP), 20,000 cP,15,000 cP, or 10,000 cP at 25 C. In some embodiments, the formulationhas a viscosity of about 5,000 cP, 6,000 cP, 7,000 cP, 8,000 cP, 9,000cP, 10,000 cP, 12,000 cP, 15,000 cP, 18,000 cP, 20,000 cP, 25,000 cP,30,000 cP, 35,000 cP, or 40,000 cP at 25 C. In some embodiments, theformulation has a viscosity of about 1,000-20,000 cP, 5,000-15,000 cP,6,000-12,000 cP, 7,000-10,000, 500-3500 cP, 500-300 cP, 1,000-2,000 cP,or about 1,500 cP at 25 C. In specific embodiments, the formulation hasa viscosity of 1,000 cP to about 2,500 cP, or about 1,500 cP at 25 C. Incertain embodiments, the amount of thickener used in a compositiondescribed herein is sufficient to achieve a viscosity as describedherein. FIG. 4 illustrates the affect of the viscosity of a formulationdescribed herein on the food intake of a subject.

In some embodiments, unit dosages of such rectal gel formulations areadministered from prefilled bags or syringes.

Rectal Suppositories

In some embodiments, the pharmaceutical compositions described hereinare also formulated as a suppository. In certain embodiments,suppositories are formulated for the regional or local non-systemicadministration of one or more enteroendocrine peptide secretionenhancing agents to the rectum and/or colon.

In some embodiments, rectal suppository formulations contain aenteroendocrine peptide secretion enhancing agent, an absorptioninhibitor (e.g., of the enteroendocrine peptide secretion enhancingagent across the rectal or colonic mucosa) and at least onepharmaceutically acceptable suppository base. In some embodiments,suppository formulation are prepared by combining an enteroendocrinepeptide secretion enhancing agent with a pharmaceutically acceptablesuppository base, melted, poured into a mould or moulds and cooled.

In certain embodiments, pharmaceutically acceptable suppository basesinclude, by way of non-limiting example, cocoa butter, beeswax,esterified fatty acids, glycerinated gelatin, semisynthetic glyceridesof vegetable saturated fatty acids, polyethylene glycols, Witepsol, andpolyoxyethylene sorbitan fatty acid esters.

In certain embodiments, the suppository formulations used to deliver oneor more enteroendocrine peptide secretion enhancing agents to the rectumand/or colon also contain one or more of the following: bufferingagents, preservatives, antioxidants, surfactants, and thickeners.

In some embodiments, suppositories contain from 0.5 to 10 mg of anenteroendocrine peptide secretion enhancing agent. In specificembodiments, suppositories contain from 1 to 5 mg of an enteroendocrinepeptide secretion enhancing agent.

Components Used in Rectal Delivery/Administration Formulations

In certain embodiments, liquid carrier vehicles in the compositionsand/or formulations described herein include, by way of non-limitingexample, purified water, propylene glycol, polyethyleneglycol, ethanol,1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol,glycerol, 2-methyl-2-propanol, formamide, methyl formamide, dimethylformamide, ethyl formamide, diethyl formamide, acetamide, methylacetamide, dimethyl acetamide, ethyl acetamide, diethyl acetamide,2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone,tetramethyl urea, 1,3-dimethyl-2-imidazolidinone, propylene carbonate,1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide,diethyl sulfoxide, hexamethyl phosphoramide, pyruvic aldehydedimethylacetal, dimethylisosorbide and combinations thereof.

In some embodiments, stabilizers used in compositions and/orformulations described herein include, but are not limited to, partialglycerides of polyoxyethylenic saturated fatty acids.

In certain embodiments, surfactants/emulsifiers used in the compositionsand/or formulations described herein include, by way of non-limitingexample, mixtures of cetostearylic alcohol with sorbitan esterified withpolyoxyethylenic fatty acids, polyoxyethylene fatty ethers,polyoxyethylene fatty esters, fatty acids, sulfated fatty acids,phosphated fatty acids, sulfosuccinates, amphoteric surfactants,non-ionic poloxamers, non-ionic meroxapols, petroleum derivatives,aliphatic amines, polysiloxane derivatives, sorbitan fatty acid esters,laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctylsodium sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol258, triethanolamine, dimethicone, polysorbate 60, sorbitanmonostearate, pharmaceutically acceptable salts thereof, andcombinations thereof.

In some embodiments, non-ionic surfactants used in compositions and/orformulations described herein include, by way of non-limiting example,phospholipids, alkyl poly(ethylene oxide), poloxamers, polysorbates,sodium dioctyl sulfosuccinate, Brij™-30 (Laureth-4), Brij™-58(Ceteth-20) and Brij™-78 (Steareth-20), Brij™-721 (Steareth-21),Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40), Crillet-3(Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40Stearate), Myrj-53 (PEG-50 Stearate), Pluronic™ F77 (Poloxamer 217),Pluronic™ F87 (Poloxamer 237), Pluronic™ F98 (Poloxamer 288), Pluronic™L62 (Poloxamer 182), Pluronic™ L64 (Poloxamer 184), Pluronic™ F68(Poloxamer 188), Pluronic™ L81 (Poloxamer 231), Pluronic™ L92 (Poloxamer282), Pluronic™ L101 (Poloxamer 331), Pluronic™ P103 (Poloxamer 333),Pluracare™ F 108 NF (Poloxamer 338), and Pluracare™ F 127 NF (Poloxamer407) and combinations thereof. Pluronic™ polymers are commerciallypurchasable from BASF, USA and Germany.

In certain embodiments, anionic surfactants used in compositions and/orformulations described herein include, by way of non-limiting example,sodium laurylsulphate, sodium dodecyl sulfate (SDS), ammonium laurylsulfate, alkyl sulfate salts, alkyl benzene sulfonate, and combinationsthereof.

In some embodiments, the cationic surfactants used in compositionsand/or formulations described herein include, by way of non-limitingexample, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, hexadecyl trimethyl ammonium bromide, otheralkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylatedtallow and combinations thereof.

In certain embodiments, the thickeners used i in compositions and/orformulations described herein include, by way of non-limiting example,natural polysaccharides, semi-synthetic polymers, synthetic polymers,and combinations thereof. Natural polysaccharides include, by way ofnon-limiting example, acacia, agar, alginates, carrageenan, guar,arabic, tragacanth gum, pectins, dextran, gellan and xanthan gums.Semi-synthetic polymers include, by way of non-limiting example,cellulose esters, modified starches, modified celluloses,carboxymethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Synthetic polymers include, by way of non-limiting example,polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates,carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones),polyvinylacetate, polyethylene glycols and poloxamer. Other thickenersinclude, by way of nonlimiting example, polyoxyethyleneglycolisostearate, cetyl alcohol, Polyglycol 300 isostearate, propyleneglycol,collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid,palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenicacid, oleic acid and the like).

In some embodiments, chelating agents used in the compositions and/orformulations described herein include, by way of non-limiting example,ethylenediaminetetraacetic acid (EDTA) or salts thereof, phosphates andcombinations thereof.

In some embodiments, the concentration of the chelating agent or agentsused in the rectal formulations described herein is a suitableconcentration, e.g., about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5%(w/v).

In some embodiments, preservatives used in compositions and/orformulations described herein include, by way of non-limiting example,parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole,butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben,methylparaben, butyl paraben, propylparaben, monothioglycerol, phenol,phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid,sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride,benzethonium chloride, benzyl alcohol, chlorhexidine acetate,chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorbutanol,phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate,thimerosol, and combnations thereof.

In certain embodiments, antioxidants used in compositions and/orformulations described herein include, by way of non-limiting example,ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehydesulfoxylate, potassium metabisulphite, sodium metabisulfite, oxygen,quinones, t-butyl hydroquinone, erythorbic acid, olive (olea eurpaea)oil, pentasodium penetetate, pentetic acid, tocopheryl, tocopherylacetate and combinations thereof.

In some embodiments, concentration of the antioxidant or antioxidantsused in the rectal formulations described herein is sufficient toachieve a desired result, e.g., about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%,0.4%, or 0.5% (w/v).

The lubricating agents used in compositions and/or formulationsdescribed herein include, by way of non-limiting example, natural orsynthetic fat or oil (e.g., a tris-fatty acid glycerate and the like).In some embodiments, lubricating agents include, by way of non-limitingexample, glycerin (also called glycerine, glycerol, 1,2,3-propanetriol,and trihydroxypropane), polyethylene glycols (PEGs), polypropyleneglycol, polyisobutene, polyethylene oxide, behenic acid, behenylalcohol, sorbitol, mannitol, lactose, polydimethylsiloxane andcombinations thereof.

In certain embodiments, mucoadhesive and/or bioadhesive polymers areused in the compositions and/or formulations described herein as agentsfor inhibiting absorption of the enteroendocrine peptide secretionenhancing agent across the rectal or colonic mucosa. Bioadhesive ormucoadhesive polymers include, by way of non-limiting example,hydroxypropyl cellulose, polyethylene oxide homopolymers, polyvinylether-maleic acid copolymers, methyl cellulose, ethyl cellulose, propylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethylcellulose, polycarbophil,polyvinylpyrrolidone, carbopol, polyurethanes, polyethyleneoxide-polypropyline oxide copolymers, sodium carboxymethyl cellulose,polyethylene, polypropylene, lectins, xanthan gum, alginates, sodiumalginate, polyacrylic acid, chitosan, hyaluronic acid and esterderivatives thereof, vinyl acetate homopolymer, calcium polycarbophil,gelatin, natural gums, karaya, tragacanth, algin, chitosan, starches,pectins, and combinations thereof.

In some embodiments, buffers/pH adjusting agents used in compositionsand/or formulations described herein include, by way of non-limitingexample, phosphoric acid, monobasic sodium or potassium phosphate,triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine,arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid,carbonate, bicarbonate, potassium metaphosphate, potassium phosphate,monobasic sodium acetate, acetic acid, acetate, citric acid, sodiumcitrate anhydrous, sodium citrate dihydrate and combinations thereof. Incertain embodiments, an acid or a base is added to adjust the pH.Suitable acids or bases include, by way of non-limiting example, HCL,NaOH and KOH.

In certain embodiments, concentration of the buffering agent or agentsused in the rectal formulations described herein is sufficient toachieve or maintain a physiologically desirable pH, e.g., about 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (w/w).

The tonicity modifiers used in compositions and/or formulationsdescribed herein include, by way of non-limiting example o, sodiumchloride, potassium chloride, sodium phosphate, mannitol, sorbitol orglucose.

Devices

In certain aspects of the methods and pharmaceutical compositionsdescribed herein, a device is used for rectal administration of thecompositions and/or formulations described herein (e.g., the rectalgels, rectal foams, ememas and suppositories described herein). Incertain embodiments, rectal gels or rectal enemas are administered usinga bag or a syringe, while rectal foams are administered using apressurized container.

In certain embodiments, a perfusion system is used to rectallyadminister the pharmaceutical compositions and/or formulations describedherein. In some embodiments, the system comprises a tube surrounded by asemi-permeable membrane is rectally inserted and a solution containing acomposition described herein is pumped into the membrane. In certainembodiments, the membrane expands to contact the rectal and/or colonwalls, wherein the enterendocrine peptide secretion enhancing agentsperfuse from the inside of the membrane to the outside. In certainembodiments, the solution is re-circulated as a continuous perfusionsystem.

Oral Administration for Colonic Delivery

In certain aspects, the composition or formulation containing one ormore enteroendocrine peptide secretion enhancing agents is orallyadministered for local delivery of an enteroendocrine peptide secretionenhancing agents to the colon and/or rectum. Unit dosage forms of suchcompositions include a pill, tablet or capsules formulated for entericdelivery to colon. In certain embodiments, such pills, tablets orcapsule contain the compositions described herein entrapped or embeddedin microspheres. In some embodiments, microspheres include, by way ofnon-limiting example, chitosan microcores HPMC capsules and celluloseacetate butyrate (CAB) microspheres. In certain embodiments, oral dosageforms are prepared using conventional methods known to those in thefield of pharmaceutical formulation. For example, in certainembodiments, tablets are manufactured using standard tablet processingprocedures and equipment. An exemplary method for forming tablets is bydirect compression of a powdered, crystalline or granular compositioncontaining the active agent(s), alone or in combination with one or morecarriers, additives, or the like. In alternative embodiments, tabletsare prepared using wet-granulation or dry-granulation processes. In someembodiments, tablets are molded rather than compressed, starting with amoist or otherwise tractable material.

In certain embodiments, tablets prepared for oral administration containvarious excipients, including, by way of non-limiting example, binders,diluents, lubricants, disintegrants, fillers, stabilizers, surfactants,preservatives, coloring agents, flavoring agents and the like. In someembodiments, binders are used to impart cohesive qualities to a tablet,ensuring that the tablet remains intact after compression. Suitablebinder materials include, by way of non-limiting example, starch(including corn starch and pregelatinized starch), gelatin, sugars(including sucrose, glucose, dextrose and lactose), polyethylene glycol,propylene glycol, waxes, and natural and synthetic gums, e.g., acaciasodium alginate, polyvinylpyrrolidone, cellulosic polymers (includinghydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, and the like),Veegum, and combinations thereof. In certain embodiments, diluents areutilized to increase the bulk of the tablet so that a practical sizetablet is provided. Suitable diluents include, by way of non-limitingexample, dicalcium phosphate, calcium sulfate, lactose, cellulose,kaolin, mannitol, sodium chloride, dry starch, powdered sugar andcombinations thereof. In certain embodiments, lubricants are used tofacilitate tablet manufacture; examples of suitable lubricants include,by way of non-limiting example, vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma,glycerin, magnesium stearate, calcium stearate, stearic acid andcombinations thereof. In some embodiments, disintegrants are used tofacilitate disintegration of the tablet, and include, by way ofnon-limiting example, starches, clays, celluloses, algins, gums,crosslinked polymers and combinations thereof. Fillers include, by wayof non-limiting example, materials such as silicon dioxide, titaniumdioxide, alumina, talc, kaolin, powdered cellulose and microcrystallinecellulose, as well as soluble materials such as mannitol, urea, sucrose,lactose, dextrose, sodium chloride and sorbitol. In certain embodiments,stabilizers are used to inhibit or retard drug decomposition reactionsthat include, by way of example, oxidative reactions. In certainembodiments, surfactants are anionic, cationic, amphoteric or nonionicsurface active agents.

In some embodiments, enteroendocrine peptide secretion enhancing agentsdescribed herein are orally administered in association with a carriersuitable for delivery of the enteroendocrine peptide secretion enhancingagents to the distal gastrointestinal tract (e.g., distal ileum, colon,and/or rectum).

In certain embodiments, a composition described herein comprises anenteroendocrine peptide secretion enhancing agent in association with amatrix (e.g., a matrix comprising hypermellose) that allows forcontrolled release of an active agent in the distal part of the ileumand/or the colon. In some embodiments, a composition comprises a polymerthat is pH sensitive (e.g., a MMX™ matrix from Cosmo Pharmaceuticals)and allows for controlled release of an active agent in the distal partof the ileum. Examples of such pH sensitive polymers suitable forcontrolled release include and are not limited to polyacrylic polymers(e.g., anionic polymers of methacrylic acid and/or methacrylic acidesters, e.g., Carbopol® polymers) that comprise acidic groups (e.g.,—COOH, —SO₃H) and swell in basic pH of the intestine (e.g., pH of abut 7to about 8). In some embodiments, a composition suitable for controlledrelease in the distal ileum comprises microparticulate active agent(e.g., micronized active agent). In some embodiments, anon-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core issuitable for delivery of an enteroendocrine peptide secretion enhancingagent (e.g., bile acid) to the distal ileum. In some embodiments, adosage form comprising an enteroendocrine peptide secretion enhancingagent (e.g., bile acid) is coated with an enteric polymer (e.g.,Eudragit® S-100, cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropylmethylcellulose phthalate, anionic polymers ofmethacrylic acid, methacrylic acid esters or the like) for site specificdelivery to the distal ileum and/or the colon. In some embodiments,bacterially activated systems are suitable for targeted delivery to thedistal part of the ileum. Examples of micro-flora activated systemsinclude dosage forms comprising pectin, galactomannan, and/or Azohydrogels and/or glycoside conjugates (e.g., conjugates ofD-galactoside,(3-D-xylopyranoside or the like) of the active agent.Examples of gastrointestinal micro-flora enzymes include bacterialglycosidases such as, for example, D-galactosidase, β-D-glucosidase,α-L-arabinofuranosidase, β-D-xylopyranosidase or the like.

The pharmaceutical composition described herein optionally include anadditional therapeutic compound described herein and one or morepharmaceutically acceptable additives such as a compatible carrier,binder, filling agent, suspending agent, flavoring agent, sweeteningagent, disintegrating agent, dispersing agent, surfactant, lubricant,colorant, diluent, solubilizer, moistening agent, plasticizer,stabilizer, penetration enhancer, wetting agent, anti-foaming agent,antioxidant, preservative, or one or more combination thereof. In someaspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound of Formula I. In oneembodiment, a compound described herein is in the form of a particle andsome or all of the particles of the compound are coated. In certainembodiments, some or all of the particles of a compound described hereinare microencapsulated. In some embodiments, the particles of thecompound described herein are not microencapsulated and are uncoated.

In certain embodiments, an oral formulation for use in any methoddescribed herein is, e.g., an enteroendocrine peptide secretionenhancing agent in association with a labile bile acid sequestrant. Alabile bile acid sequestrant is a bile acid sequestrant with a labileaffinity for bile acids. In certain embodiments, a bile acid sequestrantdescribed herein is an agent that sequesters (e.g., absorbs or ischarged with) bile acid, and/or the salts thereof.

In specific embodiments, the labile bile acid sequestrant is an agentthat sequesters (e.g., absorbs or is charged with) bile acid, and/or thesalts thereof, and releases at least a portion of the absorbed orcharged bile acid, and/or salts thereof in the distal gastrointestinaltract (e.g., the colon, ascending colon, sigmoid colon, distal colon,rectum, or any combination thereof). In certain embodiments, the labilebile acid sequestrant is an enzyme dependent bile acid sequestrant. Inspecific embodiments, the enzyme is a bacterial enzyme. In someembodiments, the enzyme is a bacterial enzyme found in highconcentration in human colon or rectum relative to the concentrationfound in the small intestine. Examples of micro-flora activated systemsinclude dosage forms comprising pectin, galactomannan, and/or Azohydrogels and/or glycoside conjugates (e.g., conjugates ofD-galactoside, β-D-xylopyranoside or the like) of the active agent.Examples of gastrointestinal micro-flora enzymes include bacterialglycosidases such as, for example, D-galactosidase, β-D-glucosidase,α-L-arabinofuranosidase, β-D-xylopyranosidase or the like. In someembodiments, the labile bile acid sequestrant is a time dependent bileacid sequestrant (i.e., the bile acid sequesters the bile acid and/orsalts thereof and after a time releases at least a portion of the bileacid and/or salts thereof). In some embodiments, a time dependent bileacid sequestrant is an agent that degrades in an aqueous environmentover time. In certain embodiments, a labile bile acid sequestrantdescribed herein is a bile acid sequestrant that has a low affinity forbile acid and/or salts thereof, thereby allowing the bile acidsequestrant to continue to sequester bile acid and/or salts thereof inan environ where the bile acids and/or salts thereof are present in highconcentration and release them in an environ wherein bile acids and/orsalts thereof are present in a lower relative concentration. In someembodiments, the labile bile acid sequestrant has a high affinity for aprimary bile acid and a low affinity for a secondary bile acid, allowingthe bile acid sequestrant to sequester a primary bile acid or saltthereof and subsequently release a secondary bile acid or salt thereofas the primary bile acid or salt thereof is converted (e.g.,metabolized) to the secondary bile acid or salt thereof. In someembodiments, the labile bile acid sequestrant is a pH dependent bileacid sequestrant. In some embodiments, the pH dependent bile acidsequestrant has a high affinity for bile acid at a pH of 6 or below anda low affinity for bile acid at a pH above 6. In certain embodiments,the pH dependent bile acid sequestrant degrades at a pH above 6.

In some embodiments, labile bile acid sequestrants described hereininclude any compound, e.g., a macro-structured compound, that cansequester bile acids and/or salts thereof through any suitablemechanism. For example, in certain embodiments, bile acid sequestrantssequester bile acids and/or salts thereof through ionic interactions,polar interactions, static interactions, hydrophobic interactions,lipophilic interactions, hydrophilic interactions, steric interactions,or the like. In certain embodiments, macrostructured compounds sequesterbile acids and/or sequestrants by trapping the bile acids and/or saltsthereof in pockets of the macrostructured compounds and, optionally,other interactions, such as those described above. In some embodiments,bile acid sequestrants (e.g., labile bile acid sequestrants) include, byway of non-limiting example, lignin, modified lignin, polymers,polycationic polymers and copolymers, polymers and/or copolymerscomprising anyone one or more of N-alkenyl-N-alkylamine residues; one ormore N,N,N-trialkyl-N—(N′-alkenylamino)alkyl-azanium residues; one ormore N,N,N-trialkyl-N-alkenyl-azanium residues; one or morealkenyl-amine residues; or a combination thereof, or any combinationthereof.

Covalent Linkage of the Drug with a Carrier

In some embodiments, strategies used for colon targeted deliveryinclude, by way of non-limiting example, covalent linkage of theenteroendocrine peptide secretion enhancing agents to a carrier, coatingthe dosage form with a pH-sensitive polymer for delivery upon reachingthe pH environment of the colon, using redox sensitive polymers, using atime released formulation, utilizing coatings that are specificallydegraded by colonic bacteria, using bioadhesive system and usingosmotically controlled drug delivery systems.

In certain embodiments of such oral administration of a compositioncontaining an enteroendocrine peptide secretion enhancing agentsdescribed herein involves covalent linking an enteroendocrine peptidesecretion enhancing agent and carrier wherein upon oral administrationthe linked moiety remains intact in the stomach and small intestine.Upon entering the colon the covalent linkage is broken by the change inpH, enzymes, and/or degradation by intestinal microflora. In certainembodiments, the covalent linkage between the enteroendocrine peptidesecretion enhancing agent and the carrier includes, by way ofnon-limiting example, azo linkage, glycoside conjugates, glucuronideconjugates, cyclodextrin conjugates, dextran conjugates, and amino-acidconjugates (high hydrophilicity and long chain length of the carrieramino acid).

Coating with Polymers: pH-Sensitive Polymers

In some embodiments, the oral dosage forms described herein are coatedwith an enteric coating to facilitate the delivery of an enteroendocrinepeptide secretion enhancing agent to the colon and/or rectum. In certainembodiments, an enteric coating is one that remains intact in the low pHenvironment of the stomach, but readily dissolved when the optimumdissolution pH of the particular coating is reached which depends uponthe chemical composition of the enteric coating. The thickness of thecoating will depend upon the solubility characteristics of the coatingmaterial. In certain embodiments, the coating thicknesses used in suchformulations described herein range from about 25 μm to about 200 μm.

In certain embodiments, the compositions or formulations describedherein are coated such that an enteroendocrine peptide secretionenhancing agent of the composition or formulation is delivered to thecolon and/or rectum without absorbing at the upper part of theintestine. In a specific embodiment, specific delivery to the colonand/or rectum is achieved by coating of the dosage form with polymersthat degrade only in the pH environment of the colon. In alternativeembodiments, the composition is coated with an enteric coat thatdissolves in the pH of the intestines and an outer layer matrix thatslowly erodes in the intestine. In some of such embodiments, the matrixslowly erodes until only a core composition comprising anenteroendocrine peptide secretion enhancing agent (and, in someembodiments, an absorption inhibitor of the agent) is left and the coreis delivered to the colon and/or rectum.

In certain embodiments, pH-dependent systems exploit the progressivelyincreasing pH along the human gastrointestinal tract (GIT) from thestomach (pH 1-2 which increases to 4 during digestion), small intestine(pH 6-7) at the site of digestion and it to 7-8 in the distal ileum. Incertain embodiments, dosage forms for oral administration of thecompositions described herein are coated with pH-sensitive polymer(s) toprovide delayed release and protect the enteroendocrine peptidesecretion enhancing agents from gastric fluid. In certain embodiments,such polymers are be able to withstand the lower pH values of thestomach and of the proximal part of the small intestine, butdisintegrate at the neutral orslightly alkaline pH of the terminal ileumand/or ileocecal junction. Thus, in certain embodiments, provided hereinis an oral dosage form comprising a coating, the coating comprising apH-senstive polymer. In some embodiments, the polymers used for colonand/or rectum targeting include, by way of non-limiting example,methacrylic acid copolymers, methacrylic acid and methyl methacrylatecopolymers, Eudragit L100, Eudragit S100, Eudragit L-30D, EudragitFS-30D, Eudragit L100-55, polyvinylacetate phthalate, hyrdoxypropylethyl cellulose phthalate, hyrdoxypropyl methyl cellulose phthalate 50,hyrdoxypropyl methyl cellulose phthalate 55, cellulose acetatetrimelliate, cellulose acetate phthalate and combinations thereof.

In certain embodiments, oral dosage forms suitable for delivery to thecolon and/or rectum comprise a coating that has a biodegradable and/orbacteria degradable polymer or polymers that are degraded by themicroflora (bacteria) in the colon. In such biodegradable systemssuitable polymers include, by way of non-limiting example, azo polymers,linear-type-segmented polyurethanes containing azo groups,polygalactomannans, pectin, glutaraldehyde crosslinked dextran,polysaccharides, amylose, guar gum, pectin, chitosan, inulin,cyclodextrins, chondroitin sulphate, dextrans, locust bean gum,chondroitin sulphate, chitosan, poly(-caprolactone), polylactic acid andpoly(lactic-co-glycolic acid).

In certain embodiments of such oral administration of compositionscontaining one or more enteroendocrine peptide secretion enhancingagents described herein, the compositions are delivered to the colonwithout absorbing at the upper part of the intestine by coating of thedosage forms with redox sensitive polymers that are degraded by themicroflora (bacteria) in the colon. In such biodegradable systems suchpolymers include, by way of non-limiting example, redox-sensitivepolymers containing an azo and/or a disulfide linkage in the backbone.

In some embodiments, compositions formulated for delivery to the colonand/or rectum are formulated for time-release. In some embodiments, timerelease formulations resist the acidic environment of the stomach,thereby delaying the release of the enteroendocrine peptide secretionenhancing agents until the dosage form enters the colon and/or rectum.

In certain embodiments the time released formulations described hereincomprise a capsule (comprising an enteroendocrine peptide secretionenhancing agent and an optional absorption inhibitor) with hydrogelplug. In certain embodiments, the capsule and hydrogel plug are coveredby a water-soluble cap and the whole unit is coated with an entericpolymer. When the capsule enters the small intestine the enteric coatingdissolves and the hydrogels plug swells and dislodges from the capsuleafter a period of time and the composition is released from the capsule.The amount of hydrogel is used to adjust the period of time to therelease the contents.

In some embodiments, provided herein is an oral dosage form comprising amulti-layered coat, wherein the coat comprises different layers ofpolymers having different pH-sensitivities. As the coated dosage formmoves along GIT the different layers dissolve depending on the pHencountered. Polymers used in such formulations include, by way ofnon-limiting example, polymethacrylates with appropriate pH dissolutioncharacteristics, Eudragit® RL and Eudragit®RS (inner layer), andEudragit® FS (outer layer). In other embodiments the dosage form is anenteric coated tablets having an outer shell of hydroxypropylcelluloseor hydroxypropylmethylcellulose acetate succinate (HPMCAS).

In some embodiments, provided herein is an oral dosage form thatcomprises coat with cellulose butyrate phthalate, cellulose hydrogenphthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate,cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate, dioxypropyl methylcellulose succinate, carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate,polymers and copolymers formed from acrylic acid, methacrylic acid, andcombinations thereof.

Combination Therapy

In certain embodiments, provided herein are combination therapies. Incertain embodiments, the compositions described herein comprise anadditional therapeutic agent. In some embodiments, the methods describedherein comprise administration of a second dosage form comprising anadditional therapeutic agent. In certain embodiments, combinationtherapies the compositions described herein are administered as part ofa regimen. Therefore, additional therapeutic agents and/or additionalpharmaceutical dosage form can be applied to a patient either directlyor indirectly, and concomitantly or sequentially, with the compositionsand formulations described herein.

In certain embodiments the compositions described herein are used incombination with at least one appetite suppressant (e.g., a 5HTtransport inhibitor, a NE transport inhibitor, a CB-1 antagonist/inverseagonist, a ghrelin antagonist, a H3 antagonist/inverse agonist, a MCH1Rantagonist, a MCH2R agonist/antagonist, a NPY1 antagonist, a NPY2agonist, a mGluR5 antagonist, leptin, a leptin agonist/modulator, aleptin derivative, an opiod antagonist, an orexin antagonist, a BRS3agonist, a CCK-A agonist, CNTF, a CNTF agonist/modulator, a CNTFderivative, a 5HT2c agonist, a Mc5r agonist, a monoamine reuptakeinhibitor, a serotonin reuptake inhibitor, a GLP-1 agonist, axokine,fenfluramine, nalmafene, phentermine, rimonabant, sibutramine,topiramate, phytopharm compound 57, and combinations thereof). Incertain embodiments the compositions or formulations described hereinare used in combination with at least one metabolic rate enhancingagents (e.g., an ACC2 inhibitor, a β3 agonist, DGAT1 inhibitor, a DGAT2inhibitor, a FAS inhibitor, a PDE inhibitor, a thyroid hormone βagonist, an UCP-1, 2, or 3 activator, an acyl-estrogen, a glucocorticoidantagonist, an 11 β HSD-1 inhibitor, a Mc3r agonist, a SCD-1,oleoyl-estrone,3-[(3,5,7-trimethyl-1-adamantyl)methyl]-6,7,8,9-tetr-ahydro-5H-[1,2,4]triazolo[4,3-a]azepine;3-(1-adamantyl)-4-ethyl-5-(e-thylthio)-4H-1,2,4-triazole;3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-de-cahydro-1,2,4-triazolo[4,3-a][11]annulene,3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazoleand combinations thereof). In some embodiments, an enteroendocrinepeptide secretion enhancing agent is combined or administered with aphosphodiesterase inhibitor. In certain embodiments, an enteroendocrinepeptide secretion enhancing agent is combined or administered withcaffeine. In certain embodiments the compositions or formulationsdescribed herein are used in combination with at least one nutrientabsorption inhibitors (e.g., a lipase inhibitor; a fatty acidtransporter inhibitor; a dicarboxylate transporter inhibitor; a glucosetransporter inhibitor; a phosphate transporter inhibitor; orlistat andcombinations thereof). In certain embodiments the compositions orformulations described herein are used in combination with at least oneappetite suppressant and at least one metabolic rate enhancing agents.In certain embodiments the compositions or formulations described hereinare used in combination with at least one appetite suppressant and atleast one nutrient absorption inhibitors. In certain embodiments thecompositions or formulations described herein are used in combinationwith at least one nutrient absorption inhibitors and at least onemetabolic rate enhancing agents. In certain embodiments the compositionsor formulations described herein are used in combination with at leastone appetite suppressant, at least one metabolic rate enhancing agentsand at least one nutrient absorption inhibitors.

In some embodiments, enteroendocrine peptide secretion enhancing agentstherapies described herein are used in combination with biliary shunttreatments. In certain embodiments, a bilary shunt is a stentedthin-walled catheter placed endoscopically within the common bile duct.In certain embodiments, the catheter runs a length down thegastrointestinal tract, providing for delivery of bile acids and/orsalts to the distal gastrointestinal tract. FIG. 16 illustratesplacement of a biliary shunt useful for delivery of endogenous bileacids and/or salts to the distal gastrointestinal tract (e.g., distalileum, colon, and/or rectum).

In some embodiments, a combination described herein comprises a DPP-4(used interchangeably herein with DPP-IV) inhibitor. In certainembodiments, a method described herein comprises administering a DPP-4inhibitor. In some instances, inhibition of DPP-IV reduces thedegradation of enteroendocrine peptide products (e.g. GLP-1) therebyprolonging the effect of GLP-1 in reducing blood glucose levels.

DPP-IV inhibitors suitable for use with the methods described hereininclude and are not limited to(2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile(vildagliptin),(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (sitagliptin),(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(saxagliptin), and2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile(alogliptin).

In some embodiments of any of the methods described herein,administration of an enteroendocrine peptide secretion enhancing agentsdescribed herein in combination with a DPP-IV inhibitor increases thelevel of GLP-1 in the blood and/or plasma of an individual by from about1.1 times to about 30 times compared to the level of GLP-1 in the bloodand/or plasma of the individual prior to administration of theenteroendocrine peptide secretion enhancing agent in combination withthe DPP-IV inhibitor. In some embodiments of any of the methodsdescribed herein, administration of an enteroendocrine peptide secretionenhancing agent described herein in combination with a DPP-IV inhibitorincreases the level of GLP-1 in the blood and/or plasma of an individualby from about 1.1 times to about 20 times compared to the level of GLP-1in the blood and/or plasma of the individual prior to administration ofthe enteroendocrine peptide secretion enhancing agent in combinationwith the DPP-IV inhibitor. In some embodiments of any of the methodsdescribed herein, administration of an enteroendocrine peptide secretionenhancing agent described herein in combination with a DPP-IV inhibitorincreases the level of GLP-1 in the blood and/or plasma of an individualby from about 1.5 times to about 10 times compared to the level of GLP-1in the blood and/or plasma of the individual prior to administration ofthe enteroendocrine peptide secretion enhancing agent in combinationwith the DPP-IV inhibitor. In some embodiments of any of the methodsdescribed herein, administration of an enteroendocrine peptide secretionenhancing agent described herein in combination with a DPP-IV inhibitorincreases the level of GLP-1 in the blood and/or plasma of an individualby from about 2 times to about 8 times compared to the level of GLP-1 inthe blood and/or plasma of the individual prior to administration of theenteroendocrine peptide secretion enhancing agent in combination withthe DPP-IV inhibitor. In some embodiments of any of the methodsdescribed herein, administration of an enteroendocrine peptide secretionenhancing agent described herein in combination with a DPP-IV inhibitorincreases the level of GLP-1 in the blood and/or plasma of an individualby from about 2 times to about 6 times compared to the level of GLP-1 inthe blood and/or plasma of the individual prior to administration of theenteroendocrine peptide secretion enhancing agent in combination withthe DPP-IV inhibitor. In some instances, an increase in GLP-1 level offrom about 2 times to about 3 times following the administration of anenteroendocrine peptide secretion enhancing agent inhibitor describedherein in combination with a DPP-IV inhibitor compared to the level ofGLP-1 in the blood and/or plasma of the individual prior toadministration of the enteroendocrine peptide secretion enhancing agentin combination with the DPP-IV inhibitor is associated with ananti-diabetic effect. In some instances, an increase in GLP-1 level offrom about 3 times to about 8 times following the administration of anenteroendocrine peptide secretion enhancing agent described herein incombination with a DPP-IV inhibitor compared to the level of GLP-1 inthe blood and/or plasma of the individual prior to administration of theenteroendocrine peptide secretion enhancing agent in combination with aDPP-IV inhibitor is associated with reduction in food intake and/orinduction of satiety and/or weight loss.

In certain embodiments of any of the methods described herein,administration of an enteroendocrine peptide secretion enhancing agentin combination with a DPP-IV inhibitor reduces blood and/or plasma sugarlevels by at least 20%, at least 30%, at least 40%, at least 50% atleast 60%, at least 70% or at least 80% compared to blood and/or plasmasugar levels prior to administration of the enteroendocrine peptidesecretion enhancing agent in combination with a DPP-IV inhibitor. Insome embodiments of any of the methods described herein, administrationof an enteroendocrine peptide secretion enhancing agent in combinationwith a DPP-IV inhibitor reduces blood and/or plasma sugar levels by atleast 20% compared to blood and/or plasma sugar levels prior toadministration of the enteroendocrine peptide secretion enhancing agentin combination with a DPP-IV inhibitor. In some embodiments of any ofthe methods described herein, administration of an enteroendocrinepeptide secretion enhancing agent in combination with a DPP-IV inhibitorreduces blood and/or plasma sugar levels by at least 30% compared toblood and/or plasma sugar levels prior to administration of theenteroendocrine peptide secretion enhancing agent in combination with aDPP-IV inhibitor. In some embodiments of any of the methods describedherein, administration of an enteroendocrine peptide secretion enhancingagent in combination with a DPP-IV inhibitor reduces blood and/or plasmasugar levels by at least 40% compared to blood and/or plasma sugarlevels prior to administration of the enteroendocrine peptide secretionenhancing agent in combination with a DPP-IV inhibitor.

In some embodiments of any of the methods described herein,administration of an enteroendocrine peptide secretion enhancing agentin combination with a DPP-IV inhibitor reduces blood and/or plasma sugarlevels for a longer period of time (e.g., at least 24 hours) compared toreduction in blood and/or plasma sugar levels upon administration ofmetformin in combination with a DPP-IV inhibitor. In some embodiments ofany of the methods described herein, administration of a single dose ofan enteroendocrine peptide secretion enhancing agent in combination witha DPP-IV inhibitor sustains reduced blood and/or plasma sugar levels forat least 6 hours, at least 12 hours, at least 14 hours, at least 16hours, at least 18 hours, at least 20 hours, at least 24 hours, at least30 hours, at least 36 hours or at least 48 hours compared to reductionin blood and/or plasma sugar levels upon administration of a single doseof metformin in combination with a DPP-IV inhibitor.

In some embodiments of any of the methods described herein,administration of an enteroendocrine peptide secretion enhancing agentin combination with a DPP-IV inhibitor results in higher levels of GLP-1in blood and/or plasma of an individual compared to levels of GLP-1 inblood and/or plasma of a normal individual. In some embodiments of anyof the methods described herein, administration of an enteroendocrinepeptide secretion enhancing agent in combination with a DPP-IV inhibitorresults in higher levels of GLP-1 in blood and/or plasma of anindividual compared to levels of GLP-1 in blood and/or plasma of anindividual undergoing therapy with metformin and/or a DPP-IV inhibitor.

Kits

In another aspect, provided herein are kits containing a device forrectal administration pre-filled a pharmaceutical composition describedherein. In certain embodiments, kits contain a device for rectaladministration and a pharmaceutical composition (e.g., a rectal dosageform) as described herein. In certain embodiments the kits includesprefilled bags for administration of rectal enemas, while in otherembodiments the kits incude prefilled bags for administration of rectalgels. In certain embodiments the kits includes prefilled syringes foradministration of rectal enemas, while in other embodiments the kitsincude prefilled syringes for administration of rectal gels. In certainembodiments the kits includes prefilled pressurized cans foradministration of rectal foams.

EXAMPLES Example 1 Rectal Foams a) 500 mM Sodium TaurocholatePreparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 26.88 grams of sodium taurocholate, 0.25grams of potassium metabisulphite, 0.3 grams EDTA (disodium salt), 0.38grams of sodium benzoate and 0.2 grams of xanthan gum are dissolved in100 mL of purified water. While stirring, 4 grams of Polysorbate 20 and4 grams of Polyglycol 300 isostearate are added and stirring iscontinued for 15 minutes. The suspension is then pumped into an aerosolcans and is immediately sealed by clinching the dispenser valve. The canis then pressurized by pumping 6.5 grams of Freon 12 and 3.5 grams ofFreon 114 into the can.

b) 500 mM Sodium Glycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 24.38 grams of sodium glycocholate, 0.25grams of potassium metabisulphite, 0.3 grams EDTA (disodium salt), 0.38grams of sodium benzoate and 0.2 grams of xanthan gum are dissolved in100 mL of purified water. While stirring, 4 grams of Polysorbate 20 and4 grams of Polyglycol 300 isostearate are added and stirring iscontinued for 15 minutes. The suspension is then pumped into an aerosolcans and is immediately sealed by clinching the dispenser valve. The canis then pressurized by pumping 6.5 grams of Freon 12 and 3.5 grams ofFreon 114 into the can.

c) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 0.25 grams of potassium metabisulphite, 0.3grams EDTA (disodium salt), 0.38 grams of sodium benzoate and 0.2 gramsof xanthan gum are dissolved in 100 mL of purified water. Whilestirring, 4 grams of Polysorbate 20 and 4 grams of Polyglycol 300isostearate are added and stirring is continued for 15 minutes. Thesuspension is then pumped into an aerosol cans and is immediately sealedby clinching the dispenser valve. The can is then pressurized by pumping6.5 grams of Freon 12 and 3.5 grams of Freon 114 into the can.

Analysis of Food Intake

The sodium taurocholate rectal foam described above is rectallyadministered to 5 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal foam without the sodium taurocholateis rectally administered to 5 conscious overnight-fasted subjects (e.g.,Sprague Dawley rats). Each subject is expoesd to pre-weighed food andthe cumulative consumption of the food is determined over a 6 hourperiod by weighing the food every 30 minutes.

The sodium glycocholate rectal foam described above is rectallyadministered to 5 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal foam without the sodium taurocholateis rectally administered to 5 conscious overnight-fasted subject (e.g.,Sprague Dawley rats). Each subject is expoesd to pre-weighed food andthe cumulative consumption of the food is determined over a 6 hourperiod by weighing the food every 30 minutes.

Example 2 Rectal Enemas a) 500 mM Sodium Taurocholate PreparationMethod:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 26.88 grams of sodium taurocholate, 0.25 grams of potassiummetabisulphite, 0.3 grams EDTA (disodium salt), 0.38 grams of sodiumbenzoate are dissolved in 100 mL of purified water and stirring iscontinued for 10 minutes. The solution is then pulled into a syringe.

b) 500 mM Sodium Glycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 24.38 grams of sodium glycocholate, 0.25grams of potassium metabisulphite, 0.3 grams EDTA (disodium salt), 0.38grams of sodium benzoate are dissolved in 100 mL of purified water andstirring is continued for 10 minutes. The solution is then pulled into asyringe.

c) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 0.25 grams of potassium metabisulphite, 0.3grams EDTA (disodium salt), 0.38 grams of sodium benzoate are dissolvedin 100 mL of purified water and stirring is continued for 10 minutes.The solution is then pulled into a syringe.

Analysis of Food Intake

The sodium taurocholate rectal enema described above is rectallyadministered to 5 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal enema without the sodiumtaurocholate is rectally administered to 5 conscious overnight-fastedsubjects (e.g., Sprague Dawley rats). Each subject is exposed topre-weighed food and the cumulative consumption of the food isdetermined over a 6 hour period by weighing the food every 30 minutes.

The sodium glycocholate rectal enema described above is rectallyadministered to 5 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal enema without the sodiumtaurocholate is rectally administered to 5 conscious overnight-fastedsubjects (e.g., Sprague Dawley rats). Each subject is exposed topre-weighed food and the cumulative consumption of the food isdetermined over a 6 hour period by weighing the food every 30 minutes.

Example 3 Rectal Suppositories a) Sodium Taurocholate PreparationMethod:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 2.69 grams of sodium taurocholate and 0.1 grams of methylcellulose are added to 10 grams of higher saturated fatty acidtriglycerides (Witepsol™ S55; Dynamic Novel Aktiengesellschaft, WestGermany) and the combination is melted at 50 C and stirred. While thecomposition is a liquid it is filled into suppository containers forrats (50 mg per container) and then quenched in ice-water.

b) 500 mM Sodium Glycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 2.69 grams of sodium glycocholate and 0.1 grams of methylcellulose are added to 10 grams of higher saturated fatty acidtriglycerides (Witepsol™ S55; Dynamic Novel Aktiengesellschaft, WestGermany) and the combination is melted at 50 C and stirred. While thecomposition is a liquid it is filled into suppository containers forrats (50 mg per container) and then quenched in ice-water.

c) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 0.1 grams of methyl cellulose is added to 10 grams of highersaturated fatty acid triglycerides (Witepsol™ S55; Dynamic NovelAktiengesellschaft, West Germany) and the combination is melted at 50 Cand stirred. While the composition is a liquid it is filled intosuppository containers for rats (50 mg per container) and then quenchedin ice-water.

Analysis of Food Intake

The sodium taurocholate rectal suppository described above is rectallyadministered to 5 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal suppository without the sodiumtaurocholate is rectally administered to 5 conscious overnight-fastedsubjects (e.g., Sprague Dawley rats). Each subject is exposed topre-weighed food and the cumulative consumption of the food isdetermined over a 6 hour period by weighing the food every 30 minutes.

The sodium glycocholate rectal suppository described above is rectallyadministered to 5 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal suppository without the sodiumglycocholate is rectally administered to 5 conscious overnight-fastedsubjects (e.g., Sprague Dawley rats). Each subject is exposed topre-weighed food and the cumulative consumption of the food isdetermined over a 6 hour period by weighing the food every 30 minutes.

Example 4 Rectal Gels—Sodium Taurocholate/Control a) 500 mM SodiumTaurocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 26.88 grams of sodium taurocholate and 1 gram of methylcellulose are dissolved in 100 mL of purified water and stirred for 15minutes. 6 syringes connected to gavage tubes were then each filled with3 mL of the composition.

b) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 1 gram of methyl cellulose is dissolved in 100 mL of purifiedwater and stirred for 15 minutes. 5 syringes connected to gavage tubesare then each filled with 3 mL of the composition.

Analysis of Food Intake

The sodium taurocholate rectal gel described above was rectallyadministered to 6 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal gel without the sodium taurocholatewas rectally administered to 5 conscious overnight-fasted subjects(e.g., Sprague Dawley rats). Each rat was then exposed to pre-weighedfood and the cumulative consumption of the food was determined over a 6hour period by weighing the food after 30 minutes, 60 minutes, 120minutes, 240 minutes and 360 minutes.

Results

The cumulative food intake in rats instilled with taurocholatecontaining gels is reduced compared to rats instilled with gel alone(FIG. 5). FIG. 5 illustrates the individual food intake in rats withbile sat containing gel per rectum (dotted lines) or control vehicle(solid lines). The effect of the taurocholate on food intake is found tobe statistically significant.

Example 5 Rectal Gels—Sodium Taurcholate Dose Response a) 50 mM SodiumTaurocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 2.688 grams of sodium taurocholate and 1 gram of methylcellulose are dissolved in 100 mL of purified water and stirred for 15minutes. 12 syringes connected to gavage tubes are then each filled with3 mL of the composition.

b) 150 mM Sodium Taurocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 8.066 grams of sodium taurocholate and 1 gram of methylcellulose are dissolved in 100 mL of purified water and stirred for 15minutes. 12 syringes connected to gavage tubes are then each filled with3 mL of the composition.

c) 500 mM Sodium Taurocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 26.88 grams of sodium taurocholate and 1 gram of methylcellulose are dissolved in 100 mL of purified water and stirred for 15minutes. 12 syringes connected to gavage tubes are then each filled with3 mL of the composition.

d) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 1 gram of methyl cellulose is dissolved in 100 mL of purifiedwater and stirred for 15 minutes. 12 syringes connected to gavage tubesare then each filled with 3 mL of the composition.

Analysis of Food Intake

A 4×4 Latin Square design is used to monitor the effect of the differentconcentration of taurocholate on the food uptake of overnight-fastedSprague Dawley rats. Each concentration is tested in triplicate withfour rats used per replicate. Therefore, twelve rats were used for eachrectal gel composition (50 mM gel, 150 mM gel, 500 mM gel and thecontrol gel), and all rats received each of the 4 treatments. Followingrectal administration of the gels, each rat is then exposed topre-weighed food and the cumulative consumption of the food isdetermined over a 24 hour period by weighing the food after 30 minutes,1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours.

Results

The cumulative food intake in rats instilled with taurocholatecontaining gels is observed to be dose dependently related to thequantity of taurocholate administered (FIG. 6). Moreover, thedifferences in food uptake are observed to be maintained for at least 24hours.

The ED50 for inhibition of food intake is obtained by plotting thnormalizing the dose response for the anorectic effect of taurocholateto the control data as a log of taurocholate dose vs the percentage ofcontrol cumulative intake (FIG. 7). The ED50 for inhibition of foodintake at 1 hour is 528 mM for 3 mL doses (1.6 mmol/rat) while for 24hour intake the ED50 is 7.2 mmol/rat. Surprisingly, the dose dependencyfor inhibition of intake is not differrent between 8 and 24 hours,thereby indicating the longevity of the anorectic response.

Example 6 Rectal Gels—Sodium Glycocholate/Control a) 500 mM SodiumGlycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 24.38 grams of sodium glucocholate and 1 gram of methylcellulose are dissolved in 100 mL of purified water and then stirred for15 minutes. 6 syringes connected to gavage tubes are then each filledwith 3 mL of the composition.

b) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 1 gram of methyl cellulose is dissolved in 100 mL of purifiedwater and stirred for 15 minutes. 5 syringes connected to gavage tubesare then each filled with 3 mL of the composition.

Analysis of Food Intake

The sodium glycocholate rectal gel described above is rectallyadministered to 6 conscious overnight-fasted subjects (e.g., SpragueDawley rats) and the control rectal gel without the sodium glycocholateis rectally administered to 5 conscious overnight-fasted subjects (e.g.,Sprague Dawley rats). Each subject is then exposed to pre-weighed foodand the cumulative consumption of the food is determined over a 6 hourperiod by weighing the food after 30 minutes, 60 minutes, 120 minutes,240 minutes and 360 minutes.

Example 7 Rectal Gels—Sodium Glycocholate Dose Response a) 50 mM SodiumGlycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 2.44 grams of sodium glycocholate and 1 gram of methyl celluloseare dissolved in 100 mL of purified water and then stirred for 15minutes. 12 syringes connected to gavage tubes are then each filled with3 mL of the composition.

b) 150 mM Sodium Glycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 7.32 grams of sodium glycocholate and 1 gram of methyl celluloseare dissolved in 100 mL of purified water and then stirred for 15minutes. 12 syringes connected to gavage tubes are then each filled with3 mL of the composition.

c) 500 mM Sodium Glycocholate Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 24.38 grams of sodium glycocholate and 1 gram of methylcellulose are dissolved in 100 mL of purified water and then stirred for15 minutes. 12 syringes connected to gavage tubes are then each filledwith 3 mL of the composition.

d) No Bile Salt (Control) Preparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer 1 gram of methyl cellulose is dissolved in 100 mL of purifiedwater and then stirred for 15 minutes. 12 syringes connected to gavagetubes are then each filled with 3 mL of the composition.

Analysis of Food Intake

A 4×4 Latin Square design as used to monitor the effect of the differentconcentration of glycocholate on the food uptake of overnight-fastedSprague Dawley rats. Each concentration is tested in triplicate withfour rats used per replicate. Therefore, twelve rats are used for eachrectal gel composition (50 mM gel, 150 mM gel, 500 mM gel and thecontrol gel), with all rats receiving each of the 4 treatments.Following rectal administration of the gels, each rat is then exposed topre-weighed food and the cumulative consumption of the food isdetermined over a 24 hour period by weighing the food after 30 minutes,1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours.

Example 8 Enteric Coated Tablets a) 5 mg Sodium Taurocholate PreparationMethod:

Preparation of core: 5 mg sodium taurocholate, 25 mg microcrystallinecellulose, 20 mg mannitol, and 10 mg croscarmellose sodium are mixed ina Hobart Mixer for 15 minutes. The mixture is granulated with 20%polyvinl pyrrolidone (4 mg) solution until optimum granulation isobtained. The granulation is dried overnight at 50° C. The granulationis then passed through a #30 mesh. The granulation is then blended with1 mg magnesium stearate. Using an F-Press ¼″ standard concave roundpunch, the granulation is compressed into a tablet. Preparation oferodible polymer layer and dual matrix tablets: 415 mg hydroxypropylmethylcellulose, 75 mg microcrystalline cellulose, and 6 mgpolyvinylpyrrolidone are uniformly mixed with a mortar. The powder mixis granulated with 50% v/v alcohol solution until optimum granulation isobtained. The granulation is dried overnight at 50° C. The granulationis then passed through a #40 mesh screen. The granulation is thenblended with 2.5 mg magnesium stearate. Using a Carver Press and a 7/16″standard concave round punch, half of the granulation is placed in thedie cavity, the core is then placed in the cavity and the other half ofthe granulation is placed in the die cavity. The mass is compressed to5,000 lbs to form the dual matrix tablet. Enteric coating: Using apropellar mixer, 42 g of hydroxypropyl methylcellulose phthalate and 4.2g of distilled acetylated monoglycerides are dissolved in 514 mL of amixture of a cetone and absolute alcohol (1:1). Using a spray system,the dual matrix tablets are then coated with the enteric coatingsolution. Approximately 60 mg of the coating material (dry basis) isapplied per tablet.

b) 500 mM Sodium Glycocholate Preparation Method:

Preparation of core: 5 mg sodium glycocholate, 25 mg microcrystallinecellulose, 20 mg mannitol, and 10 mg croscarmellose sodium are mixed ina Hobart Mixer for 15 minutes. The mixture is granulated with 20%polyvinl pyrrolidone (4 mg) solution until optimum granulation isobtained. The granulation is dried overnight at 50° C. The granulationis then passed through a #30 mesh. The granulation is then blended with1 mg magnesium stearate. Using an F-Press ¼″ standard concave roundpunch, the granulation is compressed into a tablet. Preparation oferodible polymer layer and dual matrix tablets: 415 mg hydroxypropylmethylcellulose, 75 mg microcrystalline cellulose, and 6 mgpolyvinylpyrrolidone are uniformly mixed with a mortar. The powder mixis granulated with 50% v/v alcohol solution until optimum granulation isobtained. The granulation is dried overnight at 50° C. The granulationis then passed through a #40 mesh screen. The granulation is thenblended with 2.5 mg magnesium stearate. Using a Carver Press and a 7/16″standard concave round punch, half of the granulation is placed in thedie cavity, the core is then placed in the cavity and the other half ofthe granulation is placed in the die cavity. The mass is compressed to5,000 lbs to form the dual matrix tablet. Enteric coating: Using apropellar mixer, 42 g of hydroxypropyl methylcellulose phthalate and 4.2g of distilled acetylated monoglycerides are dissolved in 514 mL of amixture of a cetone and absolute alcohol (1:1). Using a spray system,the dual matrix tablets are then coated with the enteric coatingsolution. Approximately 60 mg of the coating material (dry basis) isapplied per tablet.

c) No Bile Salt (Control) Preparation Method:

Preparation of core: 25 mg microcrystalline cellulose, 20 mg mannitol,and 10 mg croscarmellose sodium are mixed in a Hobart Mixer for 15minutes. The mixture is granulated with 20% polyvinl pyrrolidone (4 mg)solution until optimum granulation is obtained. The granulation is driedovernight at 50° C. The granulation is then passed through a #30 mesh.The granulation is then blended with 1 mg magnesium stearate. Using anF-Press ¼″ standard concave round punch, the granulation is compressedinto a tablet. Preparation of erodible polymer layer and dual matrixtablets: 415 mg hydroxypropyl methylcellulose, 75 mg microcrystallinecellulose, and 6 mg polyvinylpyrrolidone are uniformly mixed with amortar. The powder mix is granulated with 50% v/v alcohol solution untiloptimum granulation is obtained. The granulation is dried overnight at50° C. The granulation is then passed through a #40 mesh screen. Thegranulation is then blended with 2.5 mg magnesium stearate. Using aCarver Press and a 7/16″ standard concave round punch, half of thegranulation is placed in the die cavity, the core is then placed in thecavity and the other half of the granulation is placed in the diecavity. The mass is compressed to 5,000 lbs to form the dual matrixtablet. Enteric coating: Using a propellar mixer, 42 g of hydroxypropylmethylcellulose phthalate and 4.2 g of distilled acetylatedmonoglycerides are dissolved in 514 mL of a mixture of a cetone andabsolute alcohol (1:1). Using a spray system, the dual matrix tabletsare then coated with the enteric coating solution. Approximately 60 mgof the coating material (dry basis) is applied per tablet.

Analysis of Food Intake

The sodium taurocholate tablet described above (or, when necessary giventhe size and identity of a subject, a similar tablet having anappropriate dose and size) is orally administered to 5 consciousovernight-fasted subjects and the control tablet without the sodiumtaurocholate is orally administered to 5 conscious overnight-fastedsubjects. Each subject is exposed to pre-weighed food and the cumulativeconsumption of the food is determined over a 6 hour period by weighingthe food every 30 minutes.

The sodium glycocholate tablet described above (or, when necessary giventhe size and identity of a subject, a similar tablet having anappropiate dose and size) is orally administered to 5 consciousovernight-fasted subjects and the control tablet without the sodiumtaurocholate is orally administered to 5 conscious overnight-fastedsubjects. Each subject is exposed to pre-weighed food and the cumulativeconsumption of the food is determined over a 6 hour period by weighingthe food every 30 minutes.

Example 9 Absorption Inhibitors a) Control: 500 mM Sodium TaurocholatePreparation Method:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 26.88 grams of sodium taurocholate, 0.25grams of potassium metabisulphite, 0.3 grams EDTA (disodium salt) and0.38 grams of sodium benzoate dissolved in 100 mL of purified water.While stirring, 4 grams of Polysorbate 20 and 4 grams of Polyglycol 300isostearate are added and stirring is continued for 15 minutes. Thesuspension is then pumped into an aerosol cans and is immediately sealedby clinching the dispenser valve. The can is then pressurized by pumping6.5 grams of Freon 12 and 3.5 grams of Freon 114 into the can.

b) 500 mM Sodium Taurocholate+Candidate Absorption Inhibitor PreparationMethod:

Using a stainless steel dissolving vessel fitted with a propellerstirrer and turboemulsifier 26.88 grams of sodium taurocholate, 0.25grams of potassium metabisulphite, 0.3 grams EDTA (disodium salt), 0.38grams of sodium benzoate and between 0.01 grams and 20 grams of acandidate absorption inhibitor are dissolved in 100 mL of purifiedwater. While stirring, 4 grams of Polysorbate 20 and 4 grams ofPolyglycol 300 isostearate are added and stirring is continued for 15minutes. The suspension is then pumped into an aerosol cans and isimmediately sealed by clinching the dispenser valve. The can is thenpressurized by pumping 6.5 grams of Freon 12 and 3.5 grams of Freon 114into the can.

Analysis of Absorption Inhibition

The foams described above are rectally administered to 5 consciousovernight-fasted subjects (e.g., Sprague Dawley rats). Each subject isexposed to pre-weighed food and the cumulative consumption of the foodis determined over a 6 hour period by weighing the food every 30minutes. Food intake is compared between the groups. The candidateabsorption inhibitor inhibits absorption of the enteroendocrine peptidesecretion enhancing agent (in this case sodium taurocholate) when theenteroendocrine peptide secretion enhancing agent is able to interactwith the L-cells for a longer period of time (i.e., when it is notsystemically absorbed), thereby reducing food intake when compared tothe control formulation.

Alternatively, the ability of the absorption inhibitor to inhibit theabsorption of the enteroendocrine peptide secretion enhancing agent (inthis case sodium taurocholate) across the colon and/or rectum mucosa isdetermined by measuring the systemic concentration of enteroendocrinepeptide secretion enhancing agent. Systemic concentration ofenteroendocrine peptide secretion enhancing agent is measured prior toadministration and at a time following administration of theenteroendocrine peptide secretion enhancing agent (e.g., after onehour). Decreased systemic concentration of the enteroendocrine peptidesecretion enhancing agent indicate that the candidate absorptioninhibitor inhibits the absorption of the enteroendocrine peptidesecretion enhancing agent.

Example 10 Method of Inhibiting Food Intake

Studies are undertaken after an overnight fast following administration(8-10 hours prior to bile salt) of 100 mg Januvia (sitagliptin), a DDP-4inhibitor that protects GLP-1 from inactivation by proteolysis. Doseescalation involves half-log increases in dose as tolerated. Planneddoses are 1, 2, 7 and 20 mmoles of deoxycholic acid. Each dose isadministered on a different day with at least three days between doses.

Subjects undergo complete physical examination with laboratoryinvestigations including complete blood count, glucose, fasting lipids,liver function tests, urea and electrolytes, prothrombin time andpartial thromboplastin time, haemoglobin A_(1C), and urinalysis.Subjects are excluded if the fasting blood glucose is >300 mg/dl, if thehaemoglobin A_(1C) is >11%, or if there are abnormal liver functiontests (such as transaminase levels >3× the upper limit of normal.

Subjects on oral medication will not receive such medication during thefasting period prior to the study or during the study period.

Subjects are studied on four separate occasions, e.g., at weeklyintervals with at least three days gap between the different occasions.Subjects are studied after an overnight (10 hour) fast. Ten hours beforethe procedure, each subject will take 100 mg oral Januvia (sitagliptin),a DDP-4 inhibitor to protect GLP-1 (7-36) amide from degradation in thecirculation. An indwelling catheter (Intracath) is placed in a forearmvein for blood sampling. An initial basal blood sample (5 ml) is takenand the catheter kept patent with normal saline. Blood samples are takeninto EDTA Vacutainers (purple top). After 15 minutes a second bloodsample (5 ml) will be collected. Placebo (vehicle) or sodiumdeoxycholate at doses of 1, 2, 7 and 20 mmoles, incorporated into 20 mLor 60 mL of 1% carboxymethyl cellulose is placed per rectum by syringe(type) over a period of one minute. Further 5 ml blood samples arecollected 10, 20, 30, 40, 50 and 60 minutes after instillation of theplacebo or deoxycholate.

In plasma samples from each time point we will measure glucose, insulin,GLP-1 (active) and PYY (total), using assay kits (Linco) from theMillipore Corporation. Measures of these hormones provide an endpointfor determining efficacy in producing reduced food intake.

In addition, measured is food intake for a two hour period after the endof the infusion study. During this period, the subjects are offered abuffet lunch with food in such excess that all appetites will besatisfied. The amount of food is quantified preprandially andpostprandially and the caloric intake calculated. Before, at the end ofthe infusion study, and two hours after presentation of a buffet lunch,appetite ratings are made on a 100 mm visual analogue scale (highervalues indicating greater appetite) with the text expressing the mostpositive and most negative ratings at each end of the scale.

Example 11

In certain instances, placing bile salts or other TGR5 agonists into therectum has several advantages and provides substantial information onthe whole process of releasing the distal gut hormones, GLP-1,oxyntomodulin and PYY. In our human studies we have demonstrated thefollowing:

-   -   Dose-responsive increase in GLP-1 and PYY levels in the        bloodstream.    -   Consequent increase in insulin secretion and reduction in        glucose levels.    -   Dose-responsive and substantial reduction in food intake.    -   Elevation of high local concentrations of bile salt in the        rectum without diarrhea.

Example 12

Studies were undertaken after an overnight fast following administration(8-10 hours prior to bile salt) of 100 mg sitagliptin, a DPP-4 inhibitorthat protects GLP-1 from inactivation by proteolysis. Dose escalationinvolved half-log increases in dose of taurocholic acid. The doses usedwere 0.66, 2.0, 6.66 and 20.0 mmoles (358, 1075, 3584, 10,754 mg) oftaurocholic acid. The taurocholic acid was administered into the rectumby syringe in a total volume of 20 ml of 1% carboxymethyl cellulose gel.Each dose was administered on a different day with at least three daysbetween doses. FIG. 9 illustrates the increase of circulating GLP-1levels following rectal administration of taurocholic acid. FIG. 10illustrates the increase of circulating PYY levels following rectaladministration of taurocholic acid

1.-12. (canceled)
 13. A method for treating obesity or diabetes in anindividual comprising non-systemically administering to the distalgastrointestinal tract of an individual in need thereof, atherapeutically effective amount of an enteroendocrine peptide secretionenhancing agent optionally formulated with a carrier.
 14. The method ofclaim 13, further comprising administering to the individual anenteroendocrine peptide absorption inhibitor, wherein theenteroendocrine peptide absorption inhibitor inhibits the absorption ofthe enteroendocrine peptide secretion enhancing agent across the rectalor colonic mucosa.
 15. The method of claim 13, wherein theenteroendocrine peptide secretion enhancing agent and carrier areadministered rectally or orally.
 16. The method of claim 13, wherein theenteroendocrine peptide secretion enhancing agent is a bile acid, bilesalt, bile acid mimic or bile salt mimic.
 17. The method of claim 13,wherein the enteroendocrine peptide secretion enhancing agent is aglucogen-like peptide secretion enhancing agent.
 18. The method of claim17, wherein the enteroendocrine peptide secretion enhancing agent is aglucogen-like peptide-1 (GLP-1) secretion enhancing agent or aglucogen-like peptide-2 (GLP-2) secretion enhancing agent.
 19. Themethod of claim 13, wherein the enteroendocrine peptide secretionenhancing agent is a pancreatic polypeptide-fold peptide secretionenhancing agent.
 20. The method of claim 19, wherein the enteroendocrinepeptide secretion enhancing agent is a peptide YY (PYY) secretionenhancing agent.
 21. The method of claim 13, wherein the enteroendocrinepeptide secretion enhancing agent is administered in association with atleast one of a cholesterol absorption inhibitor, a spreading agent or awetting agent.
 22. The method of claim 13, wherein the absorptioninhibitor is a mucoadhesive agent.
 23. The method of claim 22, whereinthe mucoadhesive agent is selected from methyl cellulose, polycarbophil,polyvinylpyrrolidone, sodium carboxymethyl cellulose, and combinationsthereof thereof.
 24. The method of claim 13, further comprising atherapeutically effective amount of a DPP-IV inhibitor. 25.-29.(canceled)